Method for synthesis of keto acids or amino acids by hydration of acetylene compound

ABSTRACT

An object of the present invention is to provide a method for synthesis of keto acids by hydration of an acetylene compound (acetylene-carboxylic acids) under mild conditions free from harmful mercury catalysts and a method for synthesis of amino acids from acetylene-carboxylic acids in a single container (one-pot or tandem synthesis). In one embodiment of the method according to the present invention for synthesis of keto acids, acetylene-carboxylic acids is hydrated in the presence of a metal salt represented by General Formula (1), 
     
       
         
         
             
             
         
       
     
     where M 1  represents an element in Group VIII, IX, or X of the periodic table, and X 1 , X 2 , or X 3  ligand represents halogen, H 2 O, or a solvent molecule, and k represents a valence of a cation species, and Y represents an anion species, and L represents a valence of the anion species, and each of K and L independently represents 1 or 2, and k×m=L×n.

TECHNICAL FIELD

The present invention relates to a method for synthesis of keto acids(including keto acid and keto acid derivative) by hydration ofacetylene-carboxylic acids in the presence of a transition metal salt ora transition metal complex.

Further, the present invention relates to a method for synthesis ofamino acids (including amino acid and amino acid derivative) fromacetylene-carboxylic acids in a single container (one-pot or tandemsynthesis) by sequentially performing hydration of acetylene-carboxylicacids and reductive amination of keto acids (including keto acid andketo acid derivative).

BACKGROUND ART

There are many studies on hydration of acetylene compound (e.g.,Non-Patent Documents 1 to 3). However, the hydration is performed in thepresence of mercury catalysts, which are harmful for humans andenvironment. It has not been reported that keto acids and keto acidderivatives (keto esters and the like) are synthesized from acetylenecompound.

[Non-Patent Document 1]

R. C. Larock et al. “In Comprehensive Organic Synthesis” Ed. 1991, 4.269

[Non-Patent Document 2]

J. March. “Advanced Organic Chemistry”, 1991, 762

[Non-Patent Document 3]

M. Beller et al. Angew. Chem., Int. Ed. 2004 43, 3368

The object of the present invention is to provide a method for synthesisof keto acids (including keto acid and keto acid derivative) byhydration of acetylene-carboxylic acids under mild conditions free fromany harmful mercury catalysts. Further, the object of the presentinvention is to provide a method for synthesis of amino acids (includingamino acid and amino acid derivative) from acetylene-carboxylic acids ina single container (one-pot or tandem synthesis) by sequentiallyperforming hydration of acetylene-carboxylic acids and reductiveamination of keto acids (including keto acid and keto acid derivative).

DISCLOSURE OF INVENTION

The inventors of the present invention diligently studied to solve theforegoing problems. As a result, they completed the present invention.

That is, in order to solve the foregoing problems, the followinginventions are adopted.

(a) A method for synthesis of keto acids, comprising the step ofhydrating acetylene-carboxylic acid in the presence of at least oneselected from a group consisting of a metal salt represented by GeneralFormula (1), a transition metal complex represented by General Formula(2), a transition metal complex represented by General Formula (3), anda transition metal complex represented by General Formula (8),

where M¹ represents an element in Group VIII, IX, or X of the periodictable, and X¹, X², or X³ ligand represents halogen, H₂O, or a solventmolecule, and k represents a valence of a cation species, and Yrepresents an anion species, and L represents a valence of the anionspecies, and each of K and L independently represents 1 or 2, andk×m=L×n,

where each of R¹ and R² independently represents a hydrogen atom or alower alkyl group, and M² represents an element in Group VIII, IX, or XIof the periodic table, and X¹ or X² ligand represents H₂O, halogen, asolvent molecule, or nitrous ligand, and X³ ligand represents halogen,H₂O, or a solvent molecule, and k represents a valence of a cationspecies, and Y represents an anion species, and L represents a valenceof the anion species, and each of K and L independently represents 1 or2, and k×m=L×n,

where each of R¹, R², R³, R⁴, and R⁵ independently represents a hydrogenatom or a lower alkyl group, and M³ represents an element in Group VIIIor IX of the periodic table, and each of X¹ and X² represents nitrousligand, and X³ represents a hydrogen atom, a carboxylic acid residue, orH₂O, and X¹ and X² may be bonded to each other, and k represents avalence of a cation species, and Y represents an anion species, and Lrepresents a valence of the anion species, and each of K and Lindependently represents 1 or 2, and k×m=L×n,

where each of R¹, R², R³, R⁴, R⁵ and R⁶ independently represents ahydrogen atom or a lower alkyl group, and M represents an element inGroup VIII of the periodic table, and each of X¹, X² and X³ representshalogen, H₂O, or a solvent molecule, and k represents a valence of acation species, and Y represents an anion species, and L represents avalence of the anion species, and each of K and L independentlyrepresents 1 or 2, and k×m=L×n.(b) The method as set forth in claim 1, wherein the metal salt is suchthat M¹ is Ru, Rh, or Ir in General Formula (1).(c) The method based on the method (a), wherein the transition metalcomplex is such that M² is Ru or Rh in General Formula (2).(d) The method based on any one of the methods (a) to (c), wherein thehydration is performed in the presence of an organic solvent which isinert in reaction.(e) A method for synthesis of amino acids, comprising the steps of:

hydrating acetylene-carboxylic acid in the presence of a metal saltrepresented by General Formula (1); and

adding a transition metal complex represented by General Formula (3) anda hydrogen and nitrogen atom donor to a reaction system of the hydratedacetylene-carboxylic acids so as to cause a reaction thereof,

where M¹ represents an element in Group VIII, IX, or X of the periodictable, and X¹, X², or X³ ligand represents halogen, H₂O, or a solventmolecule, and k represents a valence of a cation species, and Yrepresents an anion species, and L represents a valence of the anionspecies, and each of K and L independently represents 1 or 2, andk×m=L×n,

where each of R¹, R², R³, R⁴, and R⁵ independently represents a hydrogenatom or a lower alkyl group, and M³ represents an element in Group VIIIor IX of the periodic table, and each of X¹ and X² represents nitrousligand, and X³ represents a hydrogen atom, a carboxylic acid residue, orH₂O and X¹ and X² may be bonded to each other, and k represents avalence of a cation species, and Y represents an anion species, and Lrepresents a valence of the anion species, and each of K and Lindependently represents 1 or 2, and k×m=L×n.(f) A method for synthesis of amino acids, comprising the steps of:

hydrating acetylene-carboxylics acid in the presence of a transitionmetal complex represented by General Formula (2); and

adding a transition metal complex represented by General Formula (3) anda nitrogen atom donor to a reaction system of the hydratedacetylene-carboxylic acids so as to cause a reaction thereof,

where each of R¹ and R² independently represents a hydrogen atom or alower alkyl group, and M² represents an element in Group VIII, IX, or Xof the periodic table, and X¹ or X² ligand represents H₂O, halogen, asolvent molecule, or nitrous ligand, and X³ ligand represents halogen,H₂O, or a solvent molecule, and k represents a valence of a cationspecies, and Y represents an anion species, and L represents a valenceof the anion species, and each of K and L independently represents 1 or2, and k×m=L×n,

where each of R¹, R², R³, R⁴, and R⁵ independently represents a hydrogenatom or a lower alkyl group, and M³ represents an element in Group VIIIor IX of the periodic table, and each of X¹ and X² represents nitrousligand, and X³ represents a hydrogen atom, a carboxylic acid residue, orH₂O, and X¹ and X² may be bonded to each other, and k represents avalence of a cation species, and Y represents an anion species, and Lrepresents a valence of the anion species, and each of K and Lindependently represents 1 or 2, and k×m=L×n.(g) A method for synthesis of amino acids, comprising the steps of:

hydrating acetylene-carboxylic acid in the presence of at least oneselected from a group consisting of a transition metal complexrepresented by General Formula (2), a transition metal complexrepresented by General Formula (3), and a transition metal complexrepresented by General Formula (8); and

adding a hydrogen and nitrogen atom donor to a reaction system of thehydrated acetylene-carboxylic acids so as to cause a reaction thereof,

where each of R¹ and R² independently represents a hydrogen atom or alower alkyl group, and M² represents an element in Group VIII, IX, or Xof the periodic table, and X¹, or X² ligand represents H₂O, halogen, asolvent molecule, or nitrous ligand, and X³ ligand represents halogen,H20, or a solvent molecule, and k represents a valence of a cationspecies, and Y represents an anion species, and L represents a valenceof the anion species, and each of K and L independently represents 1 or2, and k×m=L×n,

where each of R¹, R², R³, R⁴, and R⁵ independently represents a hydrogenatom or a lower alkyl group, and M³ represents an element in Group VIIIor IX of the periodic table, and each of X¹ and X² represents nitrousligand, and X³ represents a hydrogen atom, a carboxylic acid residue, orH₂O, and X¹ and X² may be bonded to each other, and k represents avalence of a cation species, and Y represents an anion species, and Lrepresents a valence of the anion species, and each of K and Lindependently represents 1 or 2, and k×m=L×n,

where each of R¹, R², R³, R⁴, R⁵ and R⁶ independently represents ahydrogen atom or a lower alkyl group, and M represents an element inGroup VIII of the periodic table, and each of X¹, X² and X³ representshalogen, H₂O, or a solvent molecule, and k represents a valence of acation species, and Y represents an anion species, and L represents avalence of the anion species, and each of K and L independentlyrepresents 1 or 2, and k×m=L×n.(h) A method for synthesis of amino acids, comprising the steps of:

hydrating acetylene-carboxylic acid in the presence of a metal saltrepresented by General Formula (1); and

adding organic ligand respectively represented by General Formula (4)and General Formula (5) and a hydrogen and nitrogen atom donor to areaction system of the hydrated acetylene-carboxylic acids so as tocause a reaction thereof,

where M¹ represents an element in Group VIII, IX, or X of the periodictable, and Xl, X2, or X³ ligand represents halogen, H₂O, or a solventmolecule, and k represents a valence of a cation species, and Yrepresents an anion species, and L represents a valence of the anionspecies, and each of K and L independently represents 1 or 2, andk×m=L×n,

where each of R¹, R², R³, R⁴, and R⁵ independently represents a hydrogenatom or a lower alkyl group,

where each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ independentlyrepresents a hydrogen atom or a lower alkyl group The hydration of thepresent invention with use of a metal salt and a transition metalcomplex allows synthesis of keto acids (including keto acid and ketoacid derivative) from acetylene-carboxylic acids under mild conditionswithout using extremely harmful mercury catalysts. The hydration isextremely useful as environmental friendly conversion. Moreover,according to the present invention, it is possible to easily synthesizeamino acids (including amino acid and amino acid derivative) from thesynthesized keto acids (including keto acid and keto acid derivative) bysubsequent reductive amination in the same container. Also in view ofcreation of a new technology, it is infinitely valuable to easilysynthesize amino acids (including amino acid and amino acid derivative)which are extremely significant in medical and biochemistry fields.

Further, the synthesis of amino acids (including amino acid and aminoacid derivative) from acetylene-carboxylic acids means also synthesis ofamino acids (including amino acid and amino acid derivative) with use ofcoal as a raw material. Currently, oil is used as a raw material tosynthesize amino acids (including amino acid and amino acid derivative).According to the present invention, it is possible to realize sucheffect that amino acids (including amino acid and amino acid derivative)can be synthesized without using oil resources whose depletion isserious concern.

For a fuller understanding of the nature and advantages of theinvention, reference should be made to the ensuing detailed descriptiontaken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1( a) is a drawing illustrating a reaction formula of synthesis ofα-keto acids (including α-keto acid and α-keto acid derivative) byhydration of acetylene-carboxylic acids in the presence of various kindsof metal salts or transmission metal complexes.

FIG. 1( b) is a drawing illustrating a reaction formula of synthesis ofβ-keto acids (including β-keto acid and β-keto acid derivative) byhydration of acetylene-carboxylic acids in the presence of various kindsof metal salts or transmission metal complexes in Examples andComparative Examples.

FIG. 2( a) is a drawing illustrating a reaction formula of synthesisamino acids (including amino acid and amino acid derivative) byreductive amination of α-keto acids (including α-keto acid and α-ketoacid derivative) in the presence of a transmission metal complexe inReferential Example.

FIG. 2( b) is a drawing illustrating a reaction formula of synthesisamino acids (including amino acid and amino acid derivative) byreductive amination of β-keto acids (including β-keto acid and β-ketoacid derivative) in the presence of a transmission metal complexe inReferential Example.

FIG. 3( a) is a drawing illustrating a reaction formula of one-potsynthesis of amino acids (including amino acid and amino acidderivative) from acetylene-carboxylic acids with use ofacetylene-carboxylic acids as starting material in Examples.

FIG. 3( b) is a drawing illustrating a reaction formula of one-potsynthesis of amino acids (including amino acid and amino acidderivative) from acetylene-carboxylic acids with use ofacetylene-carboxylic acids as starting material in Examples.

BEST MODE FOR CARRYING OUT THE INVENTION

The following explains an embodiment of the present invention. Notethat, the present invention is not limited to this.

First, a metal salt (transition metal salt) and a transition metalcomplex that are used in the present invention are explained as follows.

<Metal Salt Represented by General Formula (1)>

In the metal salt represented by General Formula (1), M¹ is notparticularly limited as long as M¹ is a transition metal element inGroup VIII, IX, or X of the periodic table, but it is preferable to use,as the transition metal element, ruthenium (hereinafter, referred to as“Ru” as necessary), rhodium (hereinafter, referred to as “Rh” asnecessary), iridium (hereinafter, referred to as “Ir” as necessary), andthe like.

Further, examples of X¹, X², or X³ ligand include H₂O, halogen, and thelike. Also a solvent molecule serves as the ligand. Examples of thesolvent molecule include methanol, ethanol, acetonitrile,tetrahydrofuran, pyridine, dimethylsulfoxide, dimethylformamide, and thelike.

Examples of an anion species represented by Y include carboxylic acidion such as formic acid and acetic acid, sulfate ion, fluoride ion,chloride ion, bromide ion, iodide ion, triflurt ion, perchloriante ion,perbromate ion, periodate ion, tetrafluoro borate ion, hexafluorophosphate ion, thiocyanate ion, and the like.

Specific examples of the metal salt represented by General Formula (1)include ruthenium trichloride, rhodium trichloride, and iridiumtrichloride. The metal salt may be an anhydride or a hydrate (e.g.,trihydrate or the like). A commercially available metal salt is used asthe aforementioned metal salt. For example, ruthenium trichloride andiridium trichloride are available from Tanaka Metal Co., Ltd. andrhodium trichloride is available from Furuya Metal Co., Ltd.

<Transition Metal Complex Represented by General Formula (2)>

In the transition metal complex represented by General Formula (2), eachof R¹ and R² independently represents a hydrogen atom or a lower alkylgroup. Examples of the lower alkyl group include an alkyl group whosecarbon number is 1-6, specifically, a methyl group, an ethyl group, apropyl group, a butyl group, a pentyl group, a hexyl group, an isopropylgroup, a t-butyl group, an isoamyl group, a cyclopentyl group, acyclohexyl group, and the like.

Further, in the transition metal complex, M² is not particularly limitedas long as M² is a transition metal element in Group VIII, IX, or X ofthe periodic table, but it is preferable to use Ru, Rh, Pd (palladium),and the like.

Further, examples of X¹ or X² ligand include H₂O, halogen, a solventmolecule, nitrous ligand, and the like. Examples of the “nitrous ligand”include pyrrole, pyridine, imidazole, N-methylimidazole, acetonitrile,ammonia, aniline, 1,2-ethanediamine, 1,2-diphenyl-1,2-ethanediamine,1,2-cyclohexadiamine, 2,2′-bipyridine, 1,10-phenanthroline, and thelike. More preferred is bidentate ligand, still more preferred is2,2′-bipyridine or a derivative thereof. Examples of the “solventmolecule” include methanol, ethanol, acetonitrile, tetrahydrofuran,pyridine, dimethylsulfoxide, dimethylformamide, and the like. Further,X³ ligand is the same as in the “metal salt represented by GeneralFormula (1)”.

Also “Y” is the same as in the “metal salt represented by GeneralFormula (1)”.

Specific examples of the transition metal complex represented by GeneralFormula (2) include di[triaqua {2,6-di(methylthiomethyl)pyridine}ruthenium (III)] 3-sulphate, di[triaqua{2,6-di(ethylthiomethyl)pyridine} ruthenium (III)] 3-sulphate,di[triaqua {2,6-di(isopropylthiomethyl) pyridine} ruthenium (III)]3-sulphate, di[triaqua {2,6-di(t-butylthiomethyl)pyridine} ruthenium(III)] 3-sulphate, di[triaqua {2,6-di(phenylthiomethyl)pyridine}ruthenium (III)] 3-sulphate, triaqua[2,6-di(methylthiomethyl) pyridine]ruthenium (III)] 3-nitrate, triaqua[2,6-di (ethylthiomethyl) pyridine]ruthenium (III)] 3-nitrate, triaqua[2,6-di(isopropylthiomethyl)pyridine] ruthenium (III)] 3-nitrate,triaqua[2,6-di (t-butylthiomethyl)pyridine] ruthenium (III)] 3-nitrate,triaqua[2,6-di (phenylthiomethyl) pyridine] ruthenium (III)] 3-nitrate,triaqua[2,6-di (methylthiomethyl) pyridine] ruthenium (III)]3-trifluoromethanesulfonate, triaqua[2,6-di(ethylthiomethyl)pyridine]ruthenium (III)] 3-trifluoromethanesulfonate,triaqua[2,6-di(isopropylthiomethyl)pyridine] ruthenium (III)]3-trifluoromethanesulfonate, triaqua[2,6-di(t-butylthiomethyl)pyridine]ruthenium (III)] 3-trifluoromethanesulfonate,triaqua[2,6-di(phenylthiomethyl)pyridine] ruthenium (III)]3-trifluoromethanesulfonate, triaqua[2,6-di(methylthiomethyl)pyridine]ruthenium (III)] 3-perchlorate, triaqua[2,6-di(ethylthiomethyl)pyridine]ruthenium (III)] 3-perchlorate,triaqua[2,6-di(isopropylthiomethyl)pyridine] ruthenium (III)]3-perchlorate, triaqua[2,6-di(t-butylthiomethyl) pyridine] ruthenium(III)] 3-perchlorate, triaqua[2,6-di(phenylthiomethyl) pyridine]ruthenium (III)] 3-perchlorate,triaqua[2,6-di(methylthiomethyl)pyridine] ruthenium (III)]3-tetrafluoroborate, triaqua[2,6-di(ethylthiomethyl) pyridine] ruthenium(III)] 3-tetrafluoroborate, triaqua[2,6-di(isopropylthiomethyl)pyridine]ruthenium (III)] 3-tetrafluoroborate,triaqua[2,6-di(t-butylthiomethyl)pyridine] ruthenium (III)]3-tetrafluoroborate, triaqua[2,6-di(phenylthiomethyl) pyridine]ruthenium (III)] 3-tetrafluoroborate, di[triaqua{2,6-di(methylthiomethyl)pyridine} rhodium (III)] 3-sulphate, di[triaqua{2,6-di(ethylthiomethyl)pyridine} rhodium (III)] 3-sulphate, di [triaqua{2,6-di(isopropylthiomethyl) pyridine} rhodium (III)] 3-sulphate,di[triaqua {2,6-di(t-butylthiomethyl) pyridine} rhodium (III)]3-sulphate, di[triaqua {2,6-di(phenylthiomethyl)pyridine} rhodium (III)]3-sulphate, triaqua[2,6-di(methylthiomethyl) pyridine] rhodium (III)]3-nitrate, triaqua[2,6-di(ethylthiomethyl)pyridine] rhodium (III)]3-nitrate, triaqua[2,6-di(isopropylthiomethyl) pyridine] rhodium (III)]3-nitrate, triaqua[2,6-di (t-butylthiomethyl)pyridine] rhodium (III)]3-nitrate, triaqua[2,6-di(phenylthiomethyl)pyridine] rhodium (III)]3-nitrate, triaqua[2,6-di(methylthiomethyl) pyridine] rhodium (III)]3-trifluoromethanesulfonate, triaqua[2,6-di(ethylthiomethyl)pyridine]rhodium (III)] 3-trifluoromethanesulfonate,triaqua[2,6-di(isopropylthiomethyl)pyridine] rhodium (III)]3-trifluoromethanesulfonate, triaqua[2,6-di(t-butylthiomethyl)pyridine]rhodium (III)] 3-trifluoromethanesulfonate,triaqua[2,6-di(phenylthiomethyl)pyridine] rhodium (III)]3-trifluoromethanesulfonate, triaqua[2,6-di(methylthiomethyl)pyridine]rhodium (III)] 3-perchlorate, triaqua[2,6-di(ethylthiomethyl)pyridine]rhodium (III)] 3-perchlorate,triaqua[2,6-di(isopropylthiomethyl)pyridine] rhodium (III)]3-perchlorate, triaqua[2,6-di(t-butylthiomethyl) pyridine] rhodium(III)] 3-perchlorate, triaqua[2,6-di(phenylthiomethyl)pyridine] rhodium(III)] 3-perchlorate, triaqua[2,6-di(methylthiomethyl) pyridine] rhodium(III)] 3-tetrafluoroborate, triaqua[2,6-di(ethylthiomethyl) pyridine]rhodium (III)] 3-tetrafluoroborate,triaqua[2,6-di(isopropylthiomethyl)pyridine] rhodium (III)]3-tetrafluoroborate, triaqua[2,6-di(t-butylthiomethyl)pyridine] rhodium(III)] 3-tetrafluoroborate, triaqua[2,6-di(phenylthiomethyl) pyridine]rhodium (III)] 3-tetrafluoroborate, and the like.

The transition metal complex represented by General Formula (2) of thepresent invention can be produced in accordance with the followingmethod for example. In the presence of water having a pH 3.8,trichloro[2,6-di(phenylthiomethyl)pyridine] ruthenium (III) is reactedwith sulfate to give di[triaqua {2,6-di(phenylthiomethyl)pyridine}ruthenium (III)] 3-sulphate. A reaction temperature is generally from−40 to 200° C., but a preferred reaction temperature is −20 to 100° C. Areaction time varies depending on reaction conditions such as a reactionsubstrate concentration, a temperature, and the like, but the reactionis generally completed in several hours to 30 hours.

Note that, also a transition metal complex obtained by substituting “N”of the transition metal complex represented by General Formula (2) with“C” and a transition metal complex obtained by substituting “S” of thetransition metal complex represented by General Formula (2) with “N” or“P” are applicable to the method of the present invention. Further, alsoa transition metal complex obtained by substituting “N” of thetransition metal complex represented by General Formula (2) with “C” andsubstituting “S” of the transition metal complex with “N” or “P” isapplicable to the method of the present invention.

<Transition Metal Complex Represented by General Formula (3)>

In a transition metal complex represented by General Formula (3),examples of R¹, R², R³, R⁴, or R⁵ lower alkyl group include an alkylgroup whose carbon number is 1-6, specifically, a methyl group, an ethylgroup, a propyl group, a butyl group, a pentyl group, a hexyl group, anisopropyl group, a t-butyl group, an isoamyl group, a cyclopentyl group,a cyclohexyl group, and the like.

Further, in the transition metal complex represented by General Formula(3), any element may be used as M³ element in Group VIII or IX of theperiodic table as long as the element is capable of forming a Cp ring(cyclopentadienyl ring). Preferred elements are Rh, Ru, Ir, and thelike.

Further, examples of nitrous ligand X¹ or X² in the transition metalcomplex represented by General Formula (3) include pyrrole, pyridine,imidazole, N-methylimidazole, acetonitrile, ammonia, aniline,1,2-ethanediamine, 1,2-diphenyl-1,2-ethanediamine, 1,2-cyclohexadiamine,2,2′-bipyridine, 1,10-phenanthroline, and the like. More preferred isbidentate ligand, still more preferred is 2,2′-bipyridine or aderivative thereof. Further, ligand X³ in the transition metal complexrepresented by General Formula (3) is a hydrogen atom, a carboxylateresidue, or H₂O. The “carboxylate residue” refers to a ligand having acarboxylic acid.

Examples of an anion species represented by Y include carboxylic acidion such as formic acid and acetic acid, sulfate ion, fluoride ion,chloride ion, bromide ion, iodide ion, triflurt ion, perchloriante ion,perbromate ion, periodate ion, tetrafluoro borate ion, hexafluorophosphate ion, thiocyanate ion, and the like.

Specific examples of the transition metal complex represented by GeneralFormula (3) include triaqua[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl]cobalt (III) sulphate, triaqua[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl]rhodium (III) sulphate, triaqua[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl]iridium (III) sulphate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]cobalt(III) sulphate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]rhodium (III) sulphate,triaqua[(1,2,3,4,5-ηl)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium (III) sulphate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]cobalt (III) 2-nitrate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]rhodium (III) 2-nitrate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1yl]iridium (III) 2-nitrate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iron (II) nitrate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]ruthenium (II) nitrate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]osmium (II) nitrate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]cobalt (III) bistrifluoromethanesulfonate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]rhodium (III) bistrifluoromethanesulfonate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium (III) bistrifluoromethanesulfonate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iron (II) trifluoromethanesulfonate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]ruthenium (II) trifluoromethanesulfonate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]osmium (II) trifluoromethanesulfonate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]cobalt (III) 2-perchlorate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]rhodium (III) 2-perchlorate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium (III) 2-perchlorate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iron (II) perchlorate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]ruthenium (II) perchlorate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]osmium (II) perchlorate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]cobalt (III) bis(tetrafluoroborate),triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]rhodium (III) bis(tetrafluoroborate),triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium (III) bis(tetrafluoroborate),triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iron (II) tetrafluoroborate, triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl] ruthenium (II)tetrafluoroborate,triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]osmium (II) tetrafluoroborate,triaqua[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl] bispyridine cobalt (III)2-perchlorate, triaqua[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl]bispyridine rhodium (III) 2-perchlorate,triaqua[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl] bispyridine iridium (III)2-perchlorate,aqua(2,2′-bipyridine)[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl] cobalt(III) 2-perchlorate, aqua(2,2′-bipyridine)[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl] rhodium (III) 2-perchlorate,aqua(2,2′-bipyridine) [(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl] iridium(III) 2-perchlorate, aqua(2,2′-bipyridine)[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl] cobalt (III) 2-perchlorate,aqua(2,2′-bipyridine)[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl] rhodium(III) 2-perchlorate, aqua(2,2′-bipyridine)[(1,2,3,4,5-η)-2,4-cyclopentadien-1-yl] rhodium (III) 2-perchlorate, andthe like.

The transition metal complex represented by General Formula (3) of thepresent invention can be produced in accordance with the followingmethod for example. In the presence of water having a pH 3.8,(η⁵-tetramethyl cyclopentadienyl) rhodium (III) triaqua complex isreacted with 2,2′-bipyridine to give (η⁵-tetramethyl cyclopentadienyl)rhodium (III) (2,2′-bipyridyl) aqua complex. A reaction temperature isgenerally from −40 to 200° C., but a preferred reaction temperature is−20 to 100° C. A reaction time varies depending on reaction conditionssuch as a reaction substrate concentration, a temperature, and the like,but the reaction is generally completed in several hours to 30 hours.

<Transition Metal Complex Represented by General Formula (8)>

In an organic metal complex represented by General Formula (8), examplesof R¹, R², R³, R⁴, R⁵, or R⁶ lower alkyl group include a methyl group,an ethyl group, a propyl group, a butyl group, a pentyl group, a hexylgroup, an isopropyl group, a t-butyl group, an isoamyl group, acyclopentyl group, a cyclohexyl group, and the like.

Further, any element may be used as M element in Group VIII of theperiodic table as long as the element is capable of forming a benzenering. Preferred is Ru.

Further, examples of X¹, X², or X³ ligand include H₂O, halogen, asolvent molecule, and the like. Examples of the solvent molecule includemethanol, ethanol, acetonitrile, tetrahydrofuran, pyridine,dimethylsulfoxide, dimethylformamide, and the like. Note that, it ispreferable that X¹, X², and X³ ligands in General Formula (8) areentirely H₂O.

Examples of an anion species represented by Y include carboxylic acidion such as formic acid and acetic acid, sulfate ion, fluoride ion,chloride ion, bromide ion, iodide ion, triflurt ion, perchloriante ion,perbromate ion, periodate ion, tetrafluoro borate ion, hexafluorophosphate ion, thiocyanate ion, and the like.

Specific examples of the organic metal complex represented by GeneralFormula (8) include triaqua-[(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl]ruthenium (II) 2-hexafluorophosphate,triaqua-[(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl] ruthenium (II)2-tetrafluoroborate, triaqua-[(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl]ruthenium (II) sulphate,triaqua-[(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl] ruthenium (II)2-formate, triaqua-[(1,2,3,4,5,6-η⁶)-cymene-1-yl] ruthenium (II)2-hexafluorophosphate, triaqua-[(1,2,3,4,5,6-η⁶)-cymene-1-yl] ruthenium(II) sulphate, triaqua-[(1,2,3,4,5,6-η⁶)-cymene-1-yl] ruthenium (II)2-formate, triaqua-[(1,2,3,4,5,6-η⁶)-cymene-1-yl] ruthenium (II)2-tetrafluoroborate,aqua-2,2′-bipyridyl-[(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl] ruthenium(II) 2-hexafluorophosphate, aqua-2,2′-bipyridyl-[(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl] ruthenium (II) 2-tetrafluoroborate,aqua-2,2′-bipyridyl-[(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl] ruthenium(II) sulphate, aqua-2,2′-bipyridyl-[(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl] ruthenium (II) formate,aqua-2,2′-bipyridyl-[(1,2,3,4,5,6-η⁶)-cymene-1-yl] ruthenium (II)hexafluorophosphate, aqua-2,2′-bipyridyl-[(1,2,3,4,5,6-η⁶)-cymene-1-yl]ruthenium (II) sulphate,aqua-2,2′-bipyridyl-[(1,2,3,4,5,6-η⁶)-cymene-1-yl] ruthenium (II)formate, aqua-2,2′-bipyridyl-[(1,2,3,4,5,6-η⁶)-cymene-1-yl] ruthenium(II) tetrafluoroborate, and the like. Preferred aretriaqua-[(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl] ruthenium (II)sulphate, triaqua-[(1,2,3,4,5,6-η⁶)-cymene-1-yl] ruthenium (II) sulfate,and the like.

The organic metal complex represented by General Formula (8) of thepresent invention can be produced in accordance with the followingmethod. That is, [(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl] ruthenium(II) trichloride is reacted with sulfate in the presence of water havinga pH 3.8 to give triaqua-[(1,2,3,4,5,6-η⁶)-hexamethylbenzene-1-yl]ruthenium (II) sulphate.

<Hydration of Acetylene-Carboxylic Acids>

One mode of the present invention is a method for synthesis of ketoacids (including keto acid and keto acid derivative) which method ischaracterized by hydration of acetylene-carboxylic acids in the presenceof at least one compound selected from a group consisting of a metalsalt represented by General Formula (1) (hereinafter, the metal salt isreferred to as “metal salt 1”), a transition metal complex representedby General Formula (2) (hereinafter, the transition metal complex isreferred to as “transition metal complex 2”), a transition metal complexrepresented by General Formula (3) (hereinafter, the transition metalcomplex is referred to as “transition metal complex 3”), and atransition metal complex represented by General Formula (8)(hereinafter, the transition metal complex is referred to as “transitionmetal complex 4”). According to the method, it is possible toefficiently perform hydration of acetylene-carboxylic acids under mildconditions. Hereinafter, a compound including keto acid and keto acidderivative is referred to as “keto acids”. The “keto acid derivative” isnot particularly limited, but examples thereof include keto-acid ester.

An example of acetylene-carboxylic acid used in the hydration of thepresent invention is a carbonyl compound represented by General Formula(6)

R¹CCCOOR²   (6)

where each of R¹ and R² independently represents a hydrogen atom, analkyl group which may be substituted and whose carbon number is 1-10, anaryl group which may be substituted and whose carbon number is 1-10, analkoxycarbonyl group which may be substituted and whose carbon number is1-10, or an aryloxycarbonyl group which may be substituted and whosecarbon number is 1-10.

Examples of the alkyl group represented by R¹ or R² of theacetylene-carboxylic acids represented by General Formula (6) include amethyl group, an ethyl group, an n-propyl group, an i-propyl group, ann-butyl group, a t-butyl group, an n-hexyl group, a cyclohexyl group, ann-heptyl group, an n-octyl group, an n-nonyl group, an n-decile group,and the like.

Specific examples of the acetylene-carboxylic acids represented byGeneral Formula (6) include propionic acid, propionate methyl,propionate ethyl, propionate isopropyl, t-butyl propionate,acetylenedicarboxylate, dimethyl acetylenedicarboxylate, diethylacetylenedicarboxylate, diisopropyl acetylenedicarboxylate,acetylenedicarboxylate di t-butyl, 2-butynate, 2-butynate methyl,2-butynate ethyl, 2-butynate isopropyl, 2-butynate t-butyl, 2-pentynate,2-pentynate methyl, 2-pentynate ethyl, 2-pentynate isopropyl,2-pentynate t-butyl, 2-hyxynate, 2-hexynate methyl, 2-hexynate ethyl,2-hexynate isopropyl, 2-hexynate t-butyl, 2-heptynate, 2-heptynatemethyl, 2-heptynate ethyl, 2-heptynate isopropyl, 2-heptynate t-butyl,2-octynate, 2-octynate methyl, 2-octynate ethyl, 2-octynate isopropyl,2-octynate t-butyl, 2-nonyate, 2-nonyoate methyl, 2-nonyoate ethyl,2-nonyoate isopropyl, 2-nonyoate t-butyl, phenylpropiolate,phenylpropiolate methyl, phenylpropiolate ethyl, phenylpropiolateisopropyl, phenylpropiolate t-butyl, and the like.

As the acetylene-carboxylic acids represented by General Formula (6),commercially available acetylene-carboxylic acids may be used. Examplesof the commercially available acetylene-carboxylic acids are products ofNacalai Tesque Co., Ltd, Tokyo Chemical Industry Co., LTD, and SigmaAldrich Japan K.K.

The hydration of the present invention allows for synthesis of keto acidand keto acid derivative corresponding to the acetylene-carboxylic acidsrepresented by General Formula (6).

Amounts of the metal salt 1, the transition metal complex 2, thetransition metal complex 3, and the transition metal complex 4 which areused in the hydration of the present invention are not particularlylimited and are suitably set in consideration for optimal conditions.Generally, a molar ratio with respect to acetylene-carboxylic acidsserving as starting material is within a range of 1 to 1/100,000roughly, preferably within a range of 1/50 to 1/10,000 roughly, inperforming the hydration.

The hydration of the present invention is performed in the presence ofor in the absence of an organic solvent dissolving the startingmaterial. Examples of the “organic solvent dissolving the startingmaterial” include: a polar solvent such as methanol, ethanol,acetonitrile, dimethylformamide, dimethylsulfoxide, and tetrahydrofuran;aliphatic hydrocarbon solvent such as hexane, cyclohexane, and heptane;aromatic hydrocarbon solvent such as benzene, toluene, and xylene;halogenated aromatic hydrocarbon solvent such as chlorobenzene anddichlorobenzene; and a mixture thereof. Basically, in view of thecatalytic activity and the product selectivity, it is more preferable toperform the hydration in the absence of the organic solvent. However,depending on cases, hydration in the presence of the organic solventdissolving the starting material allows the reaction to proceed.

In the hydration of the present invention, the pH is not particularlylimited and is suitably set in consideration for optimal conditions.However, for such reason that the metal salt 1, the transition metalcomplex 2, the transition metal complex 3, and the transition metalcomplex 4 can stably exist in water, the pH in the hydration of thepresent invention is preferably 1 to 5, more preferably 1 to 3.

The hydration of the present invention is performed generally at atemperature ranging from −90 to 200° C., but preferably from 20 to 100°C., more preferably from 80 to 100° C. Also the reaction temperature issuitably set in consideration for optimal conditions.

Further, a reaction time varies depending on reaction conditions such asa reaction substrate concentration, a temperature, and the like, but itis general that the reaction is completed in several hours to about 30hours.

How to isolate a target product and how to purify the target productafter completion of the hydration of the present invention are notparticularly limited, and the isolation and the purification can becarried out by suitably adopting known methods. For example, aftercompletion of the hydration, the solvent and an unreacted raw materialare distilled and the distilled solvent and material are washed withwater and evaporated. Further, the metal salt or the transition metalcomplex used as a catalyst can be removed by the washing with water, theevaporation, and a treatment such as adsorption and the like. Further,the hydration is performed while the metal salt or the transition metalcomplex serving as a catalyst is held by a suitable support such assilica gel, activated white clay, and the like, so that the metal saltor the transition metal complex fixed on the support can be removed byfiltration after completion of the reaction. Further, the thus collectedmetal salt or transition metal complex can be reused.

<Reductive Amination of Keto Acids>

The method according to the present invention for synthesis of aminoacids (including amino acid and amino acid derivative) (hereinafter,this method is suitably referred to as “amino acid synthesis method ofthe present invention”) may include the step of performing reductiveamination of keto acids in the presence of the transition metal complex3 and a hydrogen and nitrogen atom donor. Hereinafter, a compoundincluding amino acid and amino acid derivative is referred to as “aminoacids”. Examples of the “amino acid derivative” include amino-acid esterand N-alkyl amino acid obtained by alkylation of an amino group.

An example of the keto acids used in the reductive amination is ketoacids represented by General Formula (7)

R¹COCOOR²   (7)

where each of R¹ and R² independently represents a hydrogen atom, analkyl group which may be substituted and whose carbon number is 1-10, anaryl group which may be substituted and whose carbon number is 1-10, analkoxycarbonyl group which may be substituted and whose carbon number is1-10, or an aryloxycarbonyl group which may be substituted and whosecarbon number is 1-10.

Examples of the alkyl group represented by R¹ or R² of the keto acidsrepresented by General Formula (7) include a methyl group, an ethylgroup, an n-propyl group, an i-propyl group, an n-butyl group, a t-butylgroup, an n-hexyl group, a cyclohexyl group, an n-heptyl group, ann-octyl group, an n-nonyl group, an n-decile group, and the like.

Specific examples of the keto acid derivative represented by GeneralFormula (7) include pyruvic acid, methyl pyruvate, ethyl pyruvate,isopropyl pyruvate, t-butyl pyruvate, phenyl pyruvate, 2-oxobutanate,2-oxobutanate methyl, 2-oxobutanate ethyl, 2-oxobutanate isopropyl,2-oxobutanate t-butyl, 3-methyl-2-oxobutanate, 3-methyl-2-oxobutanatemethyl, 3-methyl-2-oxobutanate ethyl, 3-methyl-2-oxobutanate isopropyl,3-methyl-2-oxobutanate t-butyl, 2-oxopentanate, 2-oxopentanate methyl,2-oxopentanate ethyl, 2-oxopentanate isopropyl, 2-oxopentanate,3-methyl-2-oxopentanate, 3-methyl-2-oxopentanate methyl,3-methyl-2-oxopentanate ethyl, 3-methyl-2-oxopentanate isopropyl,3-methyl-2-oxopentanate t-butyl, 4-methyl-2-oxopentanate,4-methyl-2-oxopentanate methyl, 4-methyl-2-oxopentanate ethyl,4-methyl-2-oxopentanate isopropyl, 4-methyl-2-oxopentanate t-butyl,2-oxohexanate, 2-oxohexanate, 2-oxohexanate methyl, 2-oxohexanate ethyl,2-oxohexanate isopropyl, 2-oxohexanate t-butyl, 2-oxooctanate,2-oxooctanate methyl, 2-oxooctanate ethyl, 2-oxooctanate isopropyl,2-oxooctanate t-butyl, phenyl pyruvate, phenyl pyruvate methyl, phenylpyruvate ethyl, phenyl pyruvate isopropyl, phenyl pyruvate t-butyl,glyoxylic acid, glyoxylate methyl, glyoxylate ethyl, glyoxylateisopropyl, glyoxyl t-butyl, phenyl glyoxylic acid, phenyl glyoxylatemethyl, phenyl glyoxylate ethyl, phenyl glyoxylate isopropyl, phenylglyoxylate t-butyl, 2-oxoglutaric acid, and the like.

The keto acids represented by General Formula (7) of the presentinvention can be obtained by oxidization of alcohol part (hydroxylgroup) of hydroxy acid for example.

The reductive amination in the amino acid synthesis method of thepresent invention allows for synthesis of amino acids corresponding tothe keto acids represented by General Formula (7).

The “hydrogen and nitrogen atom donor” used in the reductive aminationin the amino acid synthesis method of the present invention is notparticularly limited as long as the donor can provide hydrogen atoms andnitrogen atoms to the keto acid derivative. Examples thereof includeformic ammonium or salt thereof, ammonia, N-alkylamines (e.g.,dimethylamine, diethylamine, diisopropylamine, and di-t-butylamine), andthe like.

An amount of the transition metal complex 3 used in the reductiveamination in the amino acid synthesis method of the present invention isnot particularly limited and is suitably set in consideration foroptimal conditions. Generally, a molar ratio with respect to keto acidsserving as starting material is within a range of 1 to 1/100,000roughly, preferably within a range of 1/50 to 1/10,000 roughly, inperforming the hydration.

The reductive amination of the present invention is performed in thepresence of or in the absence of the organic solvent dissolving thestarting material. Examples of the “organic solvent dissolving thestarting material” include: a polar solvent such as methanol, ethanol,acetonitrile, dimethylformamide, dimethylsulfoxide, and tetrahydrofuran;aliphatic hydrocarbon solvent such as hexane, cyclohexane, and heptane;aromatic hydrocarbon solvent such as benzene, toluene, and xylene;halogenated aromatic hydrocarbon solvent such as chlorobenzene anddichlorobenzene; and a mixture thereof. Basically, in view of thecatalytic activity and the product selectivity, it is more preferable toperform the hydration in the absence of the organic solvent. However,depending on cases, hydration in the presence of the organic solventdissolving the starting material allows the reaction to proceed.

In the reductive amination in the amino acid synthesis method of thepresent invention, the pH is not particularly limited and is suitablyset in consideration for optimal conditions. However, for such reasonthat a hydride complex generated by reaction of the transition metalcomplex 3 and formic acid ions is stable when the pH is within theaforementioned range (particularly, pH 4.5 to 7), the pH in thereductive amination is preferably 1 to 10, more preferably 3 to 7, stillmore preferably 4.5 to 7. Note that, the hydride complex is acatalytically active species of the reductive amination.

The reductive amination in the amino acid synthesis method of thepresent invention is performed generally at a temperature ranging from 0to 200° C., but preferably from 60 to 80° C. Also the reactiontemperature is suitably set in consideration for optimal conditions.

Further, a reaction time varies depending on reaction conditions such asa reaction substrate concentration, a temperature, and the like, but itis general that the reaction is completed in several hours to about 30hours.

How to isolate a target product and how to purify the target productafter completion of the hydration of the present invention are notparticularly limited, and the isolation and the purification can becarried out by suitably adopting known methods. For example, aftercompletion of the hydration, the solvent and an unreacted raw materialare distilled and the distilled solvent and material are washed withwater and evaporated. Further, the metal salt or the transition metalcomplex used as a catalyst can be removed by the washing with water, theevaporation, and a treatment such as adsorption and the like. Further,hydration is performed while the metal salt or the transition metalcomplex serving as a catalyst is held by a suitable support such assilica gel, activated white clay, and the like, so that the metal saltor the transition metal complex fixed on the support can be removed byfiltration after completion of the reaction. Further, the thus collectedmetal salt or transition metal complex can be reused.

<Method for Synthesis of Amino Acids from Acetylene-Carboxylic AcidsWith a Catalyst in the Same Reaction Vessel (One-Pot Synthesis)>

One embodiment according to the present invention for synthesis of aminoacids is a method which is characterized in that acetylene-carboxylicacids are hydrated in the presence of at least one compound selectedfrom a group consisting of the metal salt 1, the transition metalcomplex 2, the transition metal complex 3, and the transition metalcomplex 4, and the transition metal complex catalyst 3 and the hydrogenand nitrogen atom donor are added to a reaction system of the hydratedacetylene-carboxylic acids to cause a reaction thereof. That is, oneembodiment of the method according to the present invention forsynthesis of amino acids is a method in which the “hydration ofacetylene-carboxylic acids” and the “reductive amination of keto acids”are sequentially performed in a single reaction vessel to synthesizeamino acids from the acetylene-carboxylic acids.

The alkyl group represented by R¹ or R² of the acetylene-carboxylicacids represented by General Formula (6) is an alkyl group whose carbonnumber is 1-10. Specific examples thereof include a methyl group, anethyl group, an n-propyl group, an i-propyl group, an n-butyl group, at-butyl group, an n-hexyl group, a cyclohexyl group, an n-heptyl group,an n-octyl group, an n-nonyl group, an n-decile group, and the like.These starting materials are used to sequentially perform reactions ofthe acetylene-carboxylic acids into amino acids.

Specific examples of the acetylene-carboxylic acids used in thesequential reactions include propiolic acids, propiolate methyl,propiolate ethyl, propiolate isopropyl, propiolate t-butyl,acetylenedicarboxylate, acetylenedicarboxylate dimethyl,acetylenedicaboxylate diethyl, acetylenedicarboxylate diisopropyl,acetylenedicarboxylate di t-butyl, 2-butynate, 2-butynate methyl,2-butynate ethyl, 2-butynate isopropyl, 2-butynate t-butyl, 2-pentynate,2-pentynate methyl, 2-pentynate ethyl, 2-pentynate isopropyl,2-pentynate t-butyl, 2-hyxynate, 2-hexynate methyl, 2-hexynate ethyl,2-hexynate isopropyl, 2-hexynate t-butyl, 2-heptynate, 2-heptynatemethyl, 2-heptynate ethyl, 2-heptynate isopropyl, 2-heptynate t-butyl,2-octynate, 2-octynate methyl, 2-octynate ethyl, 2-octynate isopropyl,2-octynate t-butyl, 2-nonyate, 2-nonyoate methyl, 2-nonyoate ethyl,2-nonyoate isopropyl, 2-nonyoate t-butyl, phenylpropiolate,phenylpropiolate methyl, phenylpropiolate ethyl, phenylpropiolateisopropyl, phenylpropiolate t-butyl, and the like.

As the acetylene-carboxylic acids represented by General Formula (6),commercially available acetylene-carboxylic acids may be used. Examplesof the commercially available acetylene-carboxylic acids are products ofNacalai Tesque Co., Ltd, Tokyo Chemical Industry Co., Ltd, and SigmaAldrich Japan K.K.

The pH in the sequential reactions of the hydration and the reductiveamination of the present invention is suitably set at the hydrationstage to be within the range described in <Hydration ofacetylene-carboxylic acids> and at the reductive amination stage to bewithin the range described in <Reductive amination of keto acids>.

Amounts of the metal salt 1, the transition metal complex 2, thetransition metal complex 3, and the transition metal complex 4 which areused in the method of the present invention for synthesis of amino acidsare not particularly limited and are suitably set in consideration foroptimal conditions. Generally, a molar ratio with respect to keto acidsserving as starting material is within a range of 1 to 1/100,000roughly, preferably within a range of 1/50 to 1/10,000 roughly, inperforming the reactions.

The amino acid synthesis of the present invention through the sequentialreactions of the hydration and the reductive amination is carried out inthe presence of or in the absence of organic sol vent dissolving thestarting material. Examples of the “organic solvent dissolving thestarting material” include: a polar solvent such as methanol, ethanol,acetonitrile, dimethylformamide, dimethylsulfoxide, and tetrahydrofuran;aliphatic hydrocarbon solvent such as hexane, cyclohexane, and heptane;aromatic hydrocarbon solvent such as benzene, toluene, and xylene;halogenated aromatic hydrocarbon solvent such as chlorobenzene anddichlorobenzene; and a mixture thereof. Basically, in view of thecatalytic activity and the product selectivity, it is more preferable toperform the hydration in the absence of the organic solvent. However,depending on cases, hydration in the presence of the organic solventdissolving the starting material allows the reaction to proceed.

The amino acid synthesis of the present invention through the sequentialreactions of the hydration and the reductive amination is performedgenerally at a temperature of 0 to 100° C., but preferably at atemperature of 60 to about 80° C. Also a reaction temperature issuitably set in consideration for optimal conditions.

Further, a reaction time varies depending on reaction conditions such asa reaction substrate concentration, a temperature, and the like, but thereaction is generally completed in several hours to 30 hours.

If amino acids are produced from acetylene-carboxylic acids in one-potsynthesis (that is, in a sequential manner with a single reactionvessel) in this way, it is not necessary to isolate and purify ketoacids, i.e., intermediate products of the amino acid synthesis. Thismakes it possible to realize such advantage that amino acids can beproduced at lower cost and in a shorter time. <Method for Synthesis ofAmino Acids From Acetylene-Carboxylic Acids With a Catalyst Synthesizedin the Same Reaction Vessel in-situ (Tandem Synthesis)>

One embodiment according to the present invention for synthesis of aminoacids may be a method characterized in that acetylene-carboxylic acidsare hydrated in the presence of the transition metal complex 2, thetransition metal complex 3, and the transition metal complex 4, and thehydrogen and nitrogen atom donor is added to a reaction system of thehydrated acetylene-carboxylic acids to cause a reaction thereof.

Further, one embodiment according to the present invention for synthesisof amino acids may be a method characterized in thatacetylene-carboxylic acids are hydrated in the presence of the metalsalt 1, and the organic ligands represented by General Formula (4) andGeneral Formula (5) and the hydrogen and nitrogen atom donor are addedto a reaction system of the hydrated acetylene-carboxylic acids to causea reaction thereof.

That is, the method is such that the “hydration of acetylene-carboxylicacids” and the “reductive amination of keto acids” are sequentiallyperformed to synthesize amino acids from the acetylene-carboylic acids.The substances and reaction conditions adopted in the synthesis are thesame as in the aforementioned one-pot synthesis, but the tandemsynthesis is characterized in that a metal catalyst is formed in thereaction system by adding the ligands and the reaction is performed withthe metal catalyst. This makes it possible to realize such advantagethat the tandem synthesis does not require any expensive metal catalystin performing the sequential reactions.

Examples of R¹, R², R³, R⁴, or R⁵ lower alkyl group in the organicligand represented by General Formula (4) and R¹, R², R³, R⁴, R⁵, R⁶,R⁷, and R⁸ lower alkyl group in the organic ligand represented byGeneral Formula (5) include an alkyl group whose carbon number is 1-6,specifically, a methyl group, an ethyl group, a propyl group, a butylgroup, a pentyl group, a hexyl group, an isopropyl group, a t-butylgroup, an isoamyl group, a cyclopentyl group, a cyclohexyl group, andthe like.

Specific examples of the organic ligand represented by General Formula(4) include 1,2,3,4,5-pentamethyl-1,3-cyclopentadiene,1,2,3,4,5-pentaethyl-1, 3-cyclopentadiene,1,2,3,4,5-pentaisopropyl-1,3-cyclopentadiene,1,2,3,4,5-penta-t-butyl-1,3-cyclopentadiene,1,2,3,4,5-pentaphenyl-1,3-cyclopentadiene, trimethyl(2,3,4,5-tetramethyl-2,4-cyclopentadiene-1-yl) silane, trimethyl(2,3,4,5-tetraethyl-2,4-cyclopentadiene-1-yl) silane, trimethyl(2,3,4,5-tetraisopropyl-2,4-cyclopentadiene-1-yl) silane, trimethyl(2,3,4,5-tetra-t-butyl-2,4-cyclopentadiene-1-yl) silane, trimethyl(2,3,4,5-tetraphenyl-2,4-cyclopentadiene-1-yl) silane, chlorodimethyl(2,3,4,5-tetramethyl-2,4-cyclopentadiene-1-yl) silane, chlorodimethyl(2,3,4,5-tetraethyl-2,4-cyclopentadiene-1-yl) silane, chlorodimethyl(2,3,4,5-tetraisopropyl-2,4-cyclopentadiene-1-yl) silane, chlorodimethyl(2,3,4,5-tetra-t-butyl-2,4-cyclopentadiene-1-yl) silane, chlorodimethyl(2,3,4,5-tetraphenyl-2,4-cyclopentadiene-1-yl) silane, 5-((t-butylamino)dimethylsilyl) -1,2,3,4-tetramethyl-1,3-cyclopentadiene,5-((t-butylamino) dimethylsilyl)-1,2,3,4-tetraethyl-1,3-cyclopentadiene,5-((t-butylamino)dimethylsilyl)-1,2,3,4-tetraisopropyl-1,3-cyclopentadiene,5-((t-butylamino)dimethylsilyl)-1,2,3,4-tetra-t-butyl-1,3-cyclopentadiene,5-((t-butylamino)dimethylsilyl)-1,2,3,4-tetraphenyl-1,3-cyclopentadiene,1-(2,3,4,5-tetramethyl-1,3-cyclopentadiene-1-ylethanone,[(2,3,4,5-tetramethyl-2,4-cyclopentadiene-1-yl) methyl]-benzene, 1,1′,1″, 1′″, 1″″-[(1,3-cyclopentadiene-1,2,3,4,5-pentayl)pentaquis(methylene)] pentaquisbenzene,1,2,4,5-tetramethyl-3-propyl-1,3-cyclopentadiene,2,3,4,5-tetraphenyl-2,4-cyclopentadiene-1-ol, and the like.

Specific examples of the organic ligand represented by General Formula(5) include 2,2′-bipyridine, 1,10-phenanthroline, 2,2′-biquinoline,2,2′-bi-1,8-naphthyridine, 6,6′-dimethyl-2,2′-bipyridine,6,6′-dicarbonitrile-2,2′-bipyridine, 6,6′-bis (chloromethyl)-2,2′bipyridine, 2,9-dimethyl-1,10-phenanthroline,4,4′-(2,9-dimethyl-1,10-phenanthroline-4,7-diiryl) bis-benzene sulfonicacid, 2,9-dimethyl-N-(2,4,6-trinitrophenyl)-1,1O-phenanthroline-5-amine, 1,10-phenanthroline-2,9-dicarboxyaldehyde,2,9-dicarboxy-1,10-phenanthroline, 2,9-dicarboxy-1,10-phenanthroline,2,9-dimethyl 4,7-diphenyl-1,10-phenanthroline,(2,2′-biquinoline)-4,4′-dicarboxylic acid,(2,2′-biquinoline)-4′-carboxylic acid, 4,4′-dimethyl-2,2′-biquinoline,5,5′-dimethyl-2,2′-bipyridine, 5,5′-dicarbonitrile-2,2′-bipyridine,5,5′-bis (chloromethyl)-2,2′ bipyridine,3,8-dimethyl-1,10-phenanthroline,4,4′-(3.8-dimethyl-1,10-phenanthroline-4,7-diiryl) bis-benzen sulfonicacid, 1,10-phenanthroline-2,9-dicarboxyaldehyde,3,8-dicarboxy-1,10-phenanthroline, 3,8-dicarboxy-1,10-phenanthroline,3,8-dimethyl 4,7-diphenyl-1,10-phenanthroline,4,4′-dimethyl-2,2′-bipyridine, 4,4′-dimethoxy-2,2′-bipyridine,4,4′-dicarbonitrile-2,2′-bipyridine, 5,5′-bis (chloromethyl) -2,2′bipyridine, 4,7-dimethyl-1,10-phenanthroline,1,10-phenanthroline-4,7-dicarboxyaldehyde,4,7-dicarboxy-1,10-phenanthroline, and the like.

As the organic ligands represented by General Formula (4) and GeneralFormula (5), commercially available organic ligands may be used.Examples of the commercially available organic ligands are products ofNacalai Tesque Co., Ltd, Tokyo Chemical Industry Co., Ltd, and SigmaAldrich Japan K.K.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention, and all suchmodifications as would be obvious to one skilled in the art are intendedto be included within the scope of the following claims.

EXAMPLES

The following Examples will further detail the present invention, butthe present invention is not limited to the Examples.

<1. Example of synthesis of keto acids (α- or β-keto acids)>

Acetylene-carboxylic acids were hydrated in the presence of variouskinds of metal salts or transition metal complexes to synthesize ketoacids (α- or β-keto acids). Each of FIG. 1( a) and FIG. 1( b) shows areaction formula of the hydration. Note that, when water-solubleacetylene-carboxylic acids were hydrated, α-keto acids were synthesized(FIG. 1( a)), and when water-insoluble acetylene-carboxylic acids werehydrated, β-keto acids were synthesized (FIG. 1( b)). For convenience indescriptions, a reaction path shown in FIG. 1( a) is referred to as“Path A” and a reaction path shown in FIG. 1( b) is referred to as “PathC”.

Example 1

0.5 mmol of water-soluble acetylene carboxylic acids whose R¹ and R² areH in FIG. 1( a) was mixed with 2 mL of aqueous solution containing 5.0μmol of ruthenium trichloride, and the mixture was reacted at the pH 2.0at 80° C. under argon atmosphere for 12 hours. The resulting mixture wascondensed to give a product. The product was analyzed by ¹H NMR.

Example 2

0.5 mmol of water-soluble acetylene carboxylic acids whose R¹ and R² areH in FIG. 1( a) was mixed with 2 mL of aqueous solution containing 5.0μmol of rhodium trichloride, and the mixture was reacted at the pH 2.0at 80° C. under argon atmosphere for 12 hours. The resulting mixture wascondensed to give a product. The product was analyzed by ¹H NMR.

Example 3

0.5 mmol of water-soluble acetylene carboxylic acids whose R¹ and R² areH in FIG. 1( a) was mixed with 2 mL of aqueous solution containing 3.1mg (2.5 μmol) of di[triaqua {2,6-di(phenylthiomethyl)pyridine} ruthenium(III)] 3-sulphate, and the mixture was reacted at the pH 2.0 at 80° C.under argon atmosphere for 12 hours. The resulting mixture was condensedto give a product. The product was analyzed by ¹H NMR.

Example 4

0.5 mmol of water-soluble acetylene carboxylic acids whose R¹ and R² areH in FIG. 1( a) was mixed with 2 mL of aqueous solution containing 3.1mg (2.5 μmol) of di[triaqua {2,6-di(phenylthiomethyl)pyridine} rhodium(III)] 3-sulphate, and the mixture was reacted at the pH 2.0 at 80° C.under argon atmosphere for 12 hours. The resulting mixture was condensedto give a product. The product was analyzed by ¹H NMR.

Comparative Example 1

The same operation as in Examples 1 to 4 except that HgSO₄ was used as acatalyst.

Example 5

0.1 mmol of water-soluble acetylene carboxylic acids whose R¹ is COOHand R² is H in FIG. 1( a) was mixed with 2 mL of aqueous solutioncontaining 5.0 μmol of ruthenium trichloride, and the mixture wasreacted at the pH 2.0 at 80° C. under argon atmosphere for 12 hours. Theresulting mixture was condensed to give a product. The product wasanalyzed by ¹H NMR.

Example 6

0.1 mmol of water-soluble acetylene carboxylic acids whose R¹ is COOHand R² is H in FIG. 1( a) was mixed with 2 mL of aqueous solutioncontaining 5.0 μmol of rhodium trichloride, and the mixture was reactedat the pH 2.0 at 80° C. under argon atmosphere for 12 hours. Theresulting mixture was condensed to give a product. The product wasanalyzed by ¹H NMR.

Example 7

0.1 mmol of water-soluble acetylene carboxylic acids whose R¹ is COOHand R² is H in FIG. 1( a) was mixed with 2 mL of aqueous solutioncontaining 3.1 mg (2.5 μμmol) of di[triaqua{2,6-di(phenylthiomethyl)pyridine} ruthenium (III)] 3-sulphate, and themixture was reacted at the pH 2.0 at 80° C. under argon atmosphere for12 hours. The resulting mixture was condensed to give a product. Theproduct was analyzed by ¹H NMR.

Example 8

0.1 mmol of water-soluble acetylene carboxylic acids whose R¹ is COOHand R² is H in FIG. 1( a) was mixed with 2 mL of aqueous solutioncontaining 3.1 mg (2.5 μmol) of di[triaqua{2,6-di(phenylthiomethyl)pyridine} rhodium (III)] 3-sulphate, and themixture was reacted at the pH 2.0 at 80° C. under argon atmosphere for12 hours. The resulting mixture was condensed to give a product. Theproduct was analyzed by ¹H NMR.

Comparative Example 2

The same operation as in Examples 5 to 8 except that HgSO₄ was used as acatalyst.

Example 9

0.1 mmol of water-soluble acetylene carboxylic acids whose R¹ is CH₃ andR² is H in FIG. 1( a) was mixed with 2 mL of aqueous solution containing5.0 μmol of ruthenium trichloride, and the mixture was reacted at the pH2.0 at 80° C. under argon atmosphere for 12 hours. The resulting mixturewas condensed to give a product. The product was analyzed by ¹H NMR.

Example 10

0.1 mmol of water-soluble acetylene carboxylic acids whose R¹ is CH₃ andR² is H in FIG. 1( a) was mixed with 2 mL of aqueous solution containing3.1 mg (2.5 μmol) of di[triaqua {2,6-di(phenylthiomethyl) pyridine}ruthenium (III)] 3-sulphate, and the mixture was reacted at the pH 2.0at 80° C. under argon atmosphere for 12 hours. The resulting mixture wascondensed to give a product. The product was analyzed by ¹H NMR.

Example 11

0.1 mmol of water-soluble acetylene carboxylic acids whose R¹ is CH₃ andR² is H in FIG. 1( a) was mixed with 2 mL of aqueous solution containing3.1 mg (2.5 μmol) of di[triaqua {2,6-di(phenylthiomethyl)pyridine}rhodium (III)] 3-sulphate, and the mixture was reacted at the pH 2.0 at80° C. under argon atmosphere for 12 hours. The resulting mixture wascondensed to give a product. The product was analyzed by ¹H NMR.

Comparative Example 3

The same operation as in Examples 9 to 11 except that HgSO₄ was used asa catalyst.

Example 12

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ isCH₃ and R² is C₂H₅ in FIG. 1( b) was mixed with 2 mL of acetic acidbuffer aqueous solution containing 5.0 μmol of ruthenium trichloride,and the mixture was reacted at the pH 4.0 at 80° C. under argonatmosphere for 12 hours. The resulting reaction mixture was extractedand condensed with chloroform to give a product. The product wasanalyzed by ¹H NMR.

Example 13

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ isCH₃ and R² is C₂Hs in FIG. 1( b) was mixed with 2 mL of acetic acidbuffer aqueous solution containing 5.0 μmol of rhodium trichloride, andthe mixture was reacted at the pH 4.0 at 80° C. under argon atmospherefor 12 hours. The resulting reaction mixture was extracted and condensedwith chloroform to give a product. The product was analyzed by ¹H NMR.

Example 14

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ isCH₃ and R² is C₂H₅ in FIG. 1( b) was mixed with 2 mL of acetic acidbuffer aqueous solution containing 3.1 mg (2.5 μmol) of di[triaqua{2,6-di(phenylthiomethyl)pyridine} ruthenium (III)] 3-sulphate, and themixture was reacted at the pH 2.0 at 80° C. under argon atmosphere for12 hours. The resulting reaction mixture was extracted and condensedwith chloroform to give a product. The product was analyzed by ¹H NMR.

Example 15

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ isCH₃ and R² is C₂H₅ in FIG. 1( b) was mixed with 2 mL of acetic acidbuffer aqueous solution containing 3.1 mg (2.5 μmol) of di[triaqua{2,6-di(phenylthiomethyl)pyridine} rhodium (III)] 3-sulphate, and themixture was reacted at the pH 2.0 at 80° C. under argon atmosphere for12 hours. The resulting reaction mixture was extracted and condensedwith chloroform to give a product. The product was analyzed by ¹H NMR.

Comparative Example 4

The same operation as in Examples 13 to 15 except that HgSO₄ was used asa catalyst.

[Results of Examples 1 to 15 and Comparative Examples 1 to 4]

Table 1 shows the results.

TABLE 1 Yield R¹ R² Cat Path TON mol % (%) Example 1 H H water-solubleRuCl₃ A 48 1 48 Example 2 H H water-soluble RhCl₃ A 19 1 19 ComparativeH H water-soluble HgSO₄ A 4 1 4 Example 1 Example 3 H H water-solublepincer A 38 1 38 Ru³⁺ Example 4 H H water-soluble pincer A 28 1 28 Rh³⁺Example 5 COOH H water-soluble RuCl₃ A 14 5 70 Example 6 COOH Hwater-soluble RhCl₃ A 8 5 40 Comparative COOH H water-soluble HgSO₄ A 55 25 Example 2 Example 7 COOH H water-soluble pincer A 15 5 78 Rh³⁺Example 8 COOH H water-soluble pincer A 11 5 57 Rh³⁺ Example 9 CH₃ Hwater-soluble RuCl₃ A 7 5 35 Comparative CH₃ H water-soluble HgSO₄ A — 5— Example 3 Example 10 CH₃ H water-soluble pincer A 6 5 28 Rh³⁺ Example11 CH₃ H water-soluble pincer A 1 5 4 Rh³⁺ Example 12 CH₃ C₂H₅water-insoluble RuCl₃ C 1 5 5 Example 13 CH₃ C₂H₅ water-insoluble RhCl₃C 8 5 40 Comparative CH₃ C₂H₅ water-insoluble HgSO₄ C — 5 — Example 4Example 14 CH₃ C₂H₅ water-insoluble pincer C 8 5 40 Rh³⁺ Example 15 CH₃C₂H₅ water-insoluble pincer C 4 5 20 Rh³⁺

In Table 1, “Cat” represents a compound used as a catalyst (the metalsalt, the transition metal complex, or HgSO₄), “TON” represents aturnover number of the catalyst, “mol %” represents mol % of thecatalyst with respect to the acetylene-carboxylic acids, and “Yield (%)”represents an yield of keto acids produced from the acetylene-carboxylicacids. Further, “−” in Table 1 shows that the reaction did not proceed.

The keto-acid yields of Examples 1 to 4 were 4.8 to 12 times higher thanthat in using mercury sulfate, i.e., a typical mercury catalyst forhydration. In this way, it was confirmed that the catalysts used inExamples have much higher catalytic activity. Particularly, the yieldsin using ruthenium trichloride and di[triaqua {2.6-di(phenylthiomethyl)pyridine} ruthenium (III) 3-sulphate were respectively 12 times and 9.5times higher than those in Comparative Examples. In this way, it wasconfirmed that these compounds have extremely high catalytic activities.

The turnover numbers of the catalysts in Examples were 4.8 to 12 timeshigher than those in Comparative Examples. In this way, it was confirmedthat the catalysts used in Examples have much higher turnover numbersand hence are excellent as catalysts. Particularly, turnover numbers ofruthenium trichloride and di[triaqua {2.6-di(phenylthiomethyl) pyridine}ruthenium (III) 3-sulphate are respectively 12 times and 9.5 timeshigher than those in Comparative Examples. In this way, it was confirmedthat the compounds are extremely excellent as a catalyst.

Further, comparison between the results of Examples 5 to 8 and theresults of Comparative Example 2, comparison between the results ofExamples 9 to 11 and the results of Comparative Example 3, andcomparison between the results of Examples 12 to 15 and the results ofComparative Example 4 show that the results of Examples were favorableand hence the method according to the present invention for synthesis ofketo acids is excellent.

Example 21

0.1 mmol of water-soluble acetylene carboxylic acids whose R¹ and R² areH in FIG. 1( a) was mixed with 2 mL of aqueous solution containing 1.0μmol of ruthenium trichloride, and the mixture was reacted at the pH 1.3at 100° C. under argon atmosphere for 12 hours. The resulting reactionmixture was condensed to give a product. The product was analyzed by ¹HNMR.

Example 22

0.1 mmol of water-soluble acetylene carboxylic acids whose R¹ and R² areH in FIG. 1( a) was mixed with 2 mL of aqueous solution containing 1.0μmol of rhodium trichloride, and the mixture was reacted at the pH 1.3at 100° C. under argon atmosphere for 12 hours. The resulting reactionmixture was condensed to give a product. The product was analyzed by ¹HNMR.

Example 23

0.1 mmol of water-soluble acetylene carboxylic acids whose R¹ and R² areH in FIG. 1( a) was mixed with 2 mL of aqueous solution containing 1.0μmol of iridium trichloride, and the mixture was reacted at the pH 1.3at 100° C. under argon atmosphere for 12 hours. The resulting reactionmixture was condensed to give a product. The product was analyzed by ¹HNMR.

Comparative Example 5

The same operation as in Examples 21 to 23 except that HgSO₄ was used asa catalyst.

Example 24

0.1 mmol of water-soluble acetylene dicarboxylic acids whose R¹ is CH₃and R² is H in FIG. 1( a) was mixed with 2 mL of aqueous solutioncontaining 1.0 μmol of ruthenium trichloride, and the mixture wasreacted at the pH 1.3 at 100° C. under argon atmosphere for 24 hours.The resulting reaction mixture was condensed to give a product. Theproduct was analyzed by ¹H NMR.

Example 25

0.1 mmol of water-soluble acetylene dicarboxylic acids whose R¹ is CH₃and R² is H in FIG. 1( a) was mixed with 2 mL of aqueous solutioncontaining 1.0 μmol of rhodium trichloride, and the mixture was reactedat the pH 1.3 at 100° C. under argon atmosphere for 24 hours. Theresulting reaction mixture was condensed to give a product. The productwas analyzed by ¹H NMR.

Example 26

0.1 mmol of water-soluble acetylene dicarboxylic acids whose R¹ is CH₃and R² is H in FIG. 1( a) was mixed with 2 mL of aqueous solutioncontaining 1.0 μmol of iridium trichloride, and the mixture was reactedat the pH 1.3 at 100° C. under argon atmosphere for 24 hours. Theresulting reaction mixture was condensed to give a product. The productwas analyzed by ¹H NMR.

Comparative Example 6

The same operation as in Examples 24 to 26 except that HgSO₄ was used asa catalyst.

Example 27

0.1 mmol of water-soluble acetylene dicarboxylic acids whose R¹ is C₆H₅and R² is H in FIG. 1( a) was mixed with 2 mL of aqueous solutioncontaining 1.0 μmol of ruthenium trichloride, and the mixture wasreacted at the pH 4.5 at 100° C. under argon atmosphere for 24 hours.The resulting reaction mixture was condensed to give a product. Theproduct was analyzed by ¹H NMR.

Comparative Example 7

The same operation as in Example 27 except that HgSO₄ was used as acatalyst.

Example 28

0.1 mmol of water-soluble acetylene dicarboxylic acids whose R¹ is COOHand R² is H in FIG. 1( a) was mixed with 2 mL of aqueous solutioncontaining 1.0 μmol of ruthenium trichloride, and the mixture wasreacted at the pH 1.3 at 100° C. under argon atmosphere for 12 hours.The resulting reaction mixture was condensed to give a product. Theproduct was analyzed by ¹H NMR.

Example 29

0.1 mmol of water-soluble acetylene dicarboxylic acids whose R¹ is C₃H₇and R² is H in FIG. 1( a) was mixed with 2 mL of aqueous solutioncontaining 1.0 μmol of ruthenium trichloride, and the mixture wasreacted at the pH 3.5 at 100° C. under argon atmosphere for 12 hours.The resulting reaction mixture was condensed to give a product. Theproduct was analyzed by ¹H NMR.

[Results of Examples 21 to 29 and Comparative Examples 5 to 7]

Table 2 shows the results. See Table 2 in the same manner as in Table 1.

TABLE 2 Yield R¹ R² Cat Path TON mol % (%) Example 21 H H water-solubleRuCl₃ A 90 1 90 Example 22 H H water-soluble RhCl₃ A 19 1 19 Example 23H H water-soluble IrCl₃ A 29 1 29 Comparative H H water-soluble HgSO₄ A7 1 7 Example 5 Example 24 CH₃ H water-soluble RuCl₃ A 51 1 51 Example25 CH₃ H water-soluble RhCl₃ A 8 1 8 Example 26 CH₃ H water-solubleIrCl₃ A 2 1 2 Comparative CH₃ H water-soluble HgSO₄ A — 1 — Example 6Example 27 C₆H₅ H water-soluble RuCl₃ A 15 1 15 Comparative C₆H₅ C₂H₅water-soluble HgSO₄ A — 1 — Example 7 Example 28 COOH C₂H₅ water-solubleRuCl₃ A 64 1 64 Example 29 C₃H₇ C₂H₅ water-soluble RuCl₃ A 24 1 24

The yields and turnover numbers of the keto acids of Examples 21 to 23were 2.7 to 13 times higher than that in Comparative Example 5 usingmercury sulfate. In this way, it was confirmed that the catalysts(ruthenium trichloride, rhodium trichloride, and iridium trichloride)used in Examples have much higher catalytic activities than that ofmercury sulfate. Particularly, the yield and turnover number in usingruthenium trichloride as a catalyst was 13 times higher than that inComparative Example 5. In this way, it was confirmed that rutheniumtrichloride is a particularly excellent catalyst in the reactions ofExamples.

Comparative Example 6 using mercury sulfate resulted in formation of noketo acids, but Examples 24 to 26 resulted in formation of keto acids.Thus, it was confirmed that the catalysts (ruthenium trichloride,rhodium trichloride, and iridium trichloride) used in Examples are muchmore excellent than mercury sulfate. Particularly, in Example 24 usingruthenium trichloride, keto acids were formed at such an extremely highyield as 51%. In this way, it was confirmed that ruthenium trichlorideis a particularly excellent catalyst in the reactions of Examples.

Comparative Example 7 using mercury sulfate resulted in formation of noketo acids, but Example 27 resulted in formation of keto acids. Thus, itwas confirmed that the catalyst (ruthenium trichloride) used in Example27 is much more excellent as a catalyst than mercury sulfate.

Also Examples 28 and 29 resulted in formation of keto acids.

Note that, Examples 21 and Example 1 are different only in a reactiontemperature, i.e., whether the reaction temperature is 100° C. or 80° C.Comparison between Example 21 and Example 1 in the keto-acid yield andturnover number shows that the keto-acid yield and turnover number areincreased by changing the reaction temperature from 80° C. to 100° C. Onthe other hand, Example 24 and Example 9 were different from each othernot only in the reaction temperature (100° C. or 80° C.) but also in aratio of acetylene-carboxylic acids and catalyst. However, although thecatalyst ratio was 1/5, the keto-acid yield and turnover number inExample 24 was about 1.5 times higher than those in Example 9. Notethat, each of the catalysts used in Examples 1, 21, 24, and 9 wasruthenium trichloride. This shows that 100° C. is more preferable than80° C. as the reaction temperature in the hydration ofacetylene-carboxylic acids with ruthenium trichloride used as acatalyst.

Example 30

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ is Hand R² is C₂H₅ in FIG. 1( b) was mixed with 2 mL of acetic acid bufferaqueous solution containing 1.0 μmol of ruthenium trichloride, and themixture was reacted at the pH 4.0 at 80° C. under argon atmosphere for12 hours. The resulting reaction mixture was extracted and condensedwith chloroform to give a product. The product was analyzed by ¹H NMR.

Example 31

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ is Hand R₂ is C₂H₅ in FIG. 1( b) was mixed with 2 mL of acetic acid bufferaqueous solution containing 1.0 μmol of rhodium trichloride, and themixture was reacted at the pH 4.0 at 80° C. under argon atmosphere for12 hours. The resulting reaction mixture was extracted and condensedwith chloroform to give a product. The product was analyzed by ¹H NMR.

Example 32

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ is Hand R² is C₂H₅ in FIG. 1( b) was mixed with 2 mL of acetic acid bufferaqueous solution containing 1.0 μmol of iridium trichloride, and themixture was reacted at the pH 4.0 at 80° C. under argon atmosphere for12 hours. The resulting reaction mixture was extracted and condensedwith chloroform to give a product. The product was analyzed by ¹H NMR.

Comparative Example 8

The same operation as in Examples 30 to 32 except that HgSO₄ was used asa catalyst.

Example 33

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ isCH₃ and R₂ is C₂H₅ in FIG. 1( b) was mixed with 2 mL of acetic acidbuffer aqueous solution containing 1.0 μmol of rhodium trichloride, andthe mixture was reacted at the pH 4.0 at 80° C. under argon atmospherefor 12 hours. The resulting reaction mixture was extracted and condensedwith chloroform to give a product. The product was analyzed by ¹H NMR.

Example 34

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ isCH₃ and R₂ is C₂H₅ in FIG. 1( b) was mixed with 2 mL of acetic acidbuffer aqueous solution containing 1.0 μmol of iridium trichloride, andthe mixture was reacted at the pH 4.0 at 80° C. under argon atmospherefor 12 hours. The resulting reaction mixture was extracted and condensedwith chloroform to give a product. The product was analyzed by ¹H NMR.

Comparative Example 9

The same operation as in Examples 33 to 34 except that HgSO₄ was used asa catalyst.

Example 35

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ isC₄H₉ and R₂ is C₂H₅ in FIG. 1( b) was mixed with 2 mL of acetic acidbuffer aqueous solution containing 10 μmol of rhodium trichloride, andthe mixture was reacted at the pH 4.0 at 80° C. under argon atmospherefor 12 hours. The resulting reaction mixture was extracted and condensedwith chloroform to give a product. The product was analyzed by ¹H NMR.

Example 36

0.1 mmol of water-insoluble acetylene dicarboxylate ester whose R¹ isC₄H₉ and R₂ is C₂H₅ in FIG. 1( b) was mixed with 2 mL of acetic acidbuffer aqueous solution containing 10 μmol of iridium trichloride, andthe mixture was reacted at the pH 4.0 at 80° C. under argon atmospherefor 12 hours. The resulting reaction mixture was extracted and condensedwith chloroform to give a product. The product was analyzed by ¹H NMR.

Comparative Example 10

The same operation as in Examples 35 to 36 except that HgSO₄ was used asa catalyst.

[Results of Examples 30 to 36 and Comparative Examples 8 to 10]

Table 3 shows the results. See Table 3 in the same manner as in Table 1.

TABLE 3 R¹ R² Cat Path TON mol % Yield (%) Example 30 H C₂H₅water-insoluble RuCl₃ C 3.4 1 3.4 Example 31 H C₂H₅ water-insolubleRhCl₃ C 2.3 1 2.3 Example 32 H C₂H₅ water-insoluble IrCl₃ C 4.9 1 4.9Comparative H C₂H₅ water-insoluble HgSO₄ C 2.0 1 2.0 Example 8 Example33 CH₃ C₂H₅ water-insoluble RhCl₃ C 12 1 12 Example 34 CH₃ C₂H₅water-insoluble IrCl₃ C 71 1 71 Comparative CH₃ C₂H₅ water-insolubleHgSO₄ C 7 1 7 Example 9 Example 35 C₄H₉ C₂H₅ water-insoluble RhCl₃ C 1.110 11 Example 36 C₄H₉ C₂H₅ water-insoluble IrCl₃ C 2.1 10 21 ComparativeC₄H₉ C₂H₅ water-insoluble HgSO₄ C 1.2 10 12 Example 10

The keto-acid ester yields and turnover numbers in Examples 30 to 32were equal to or higher than that in Comparative Example 8 using mercurysulfate. This shows that the present invention allows for synthesis ofketo acids by hydration of an acetylene compound under mild conditionsfree from any harmful mercury catalysts.

The keto-acid ester yields and turnover numbers in Examples 33 to 34were higher than Comparative Example 9 using mercury sulfate. This showsthat the catalysts (ruthenium trichloride, rhodium trichloride, andiridium trichloride) used in Examples are much more excellent thanmercury sulfate. Particularly, in Example 34 using rhodium trichloride,keto acids were formed at such an extremely high yield as 71%. In thisway, it was confirmed that rhodium trichloride is a particularlyexcellent catalyst in the reactions of Examples.

The keto-acid ester yields and turnover numbers in Examples 35 to 36were equal to or higher than Comparative Example 10 using mercurysulfate. This shows that the present invention allows for synthesis ofketo acids by hydration of an acetylene compound under mild conditionsfree from any harmful mercury catalyst.

<2. Synthesis of Amino Acid and Amino Acid Derivative>

Reductive amination of keto acids was performed in the presence of atransition metal complex to synthesize amino acids. Each of FIG. 2( a)and FIG. 2( b) shows a reaction formula of the reductive amination. Notethat, when reductive amination of α-keto acids was performed, α-aminoacids and α-hydroxy-carboxylic acids were synthesized (FIG. 2( a)), andwhen reductive amination of β-keto acids was performed, β-amino acidsand β-hydroxy-carboxylic acids were synthesized (FIG. 2( b)). Forconvenience in descriptions, a reaction path shown in FIG. 2( a) isreferred to as “Path B” and a reaction path shown in FIG. 2( b) isreferred to as “Path D”.

Referential Example 1

0.16 mmol of pyruvic acid whose R¹ is CH₃ and R² is H in FIG. 2( a) and3.2 mmol of formate ammonium were poured into 3 mL of water so as tohave the pH 4.5. 0.2 μmol of (η⁵-tetramethylcyclopentadienyl) rhodium(III) (2,2′-bipyridyl) aqua complex was added to the pyruvic acidaqueous solution, and the resulting mixture was reacted at 80° C. underargon atmosphere for an hour. After completion of the reaction, theresulting product was analyzed by ¹H NMR. In isolation of the product,the reaction solution was condensed, and the condensed residue wasdissolved in water, and the resulting water was made to pass through acation exchange resin (DOWEX 50W-X2). After flowing 50 mL of water, 200mL of 0.1 M aqueous ammonia was flown, and the solution was condensed togive a product (alanine).

Referential Example 2

0.16 mmol of 4-hydroxy pyruvic acid whose R¹ is C₆H₄ (OH) and R² is H inFIG. 2( a) and 3.2 mmol of formate ammonium were poured into 3 mL ofwater so as to have the pH 4.5. 0.2 μmol of(η⁵-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl) aquacomplex was added to the pyruvic acid aqueous solution, and theresulting mixture was reacted at 80° C. under argon atmosphere for anhour. After completion of the reaction, the resulting product wasanalyzed by ¹H NMR. In isolation of the product, the reaction mixturewas filtrated to give tyrosine, i.e., a reaction product.

Referential Example 3

0.16 mmol of keto glutaric acid whose R¹ is (CH₂)₂COOH and R² is H inFIG. 2( a) and 3.2 mmol of formate ammonium were poured into 3 mL ofwater so as to have the pH 4.5. 0.2 μmol of(η⁵-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl) aquacomplex was added to the pyruvic acid aqueous solution, and theresulting mixture was reacted at 80° C. under argon atmosphere for anhour. After completion of the reaction, the resulting product wasanalyzed by ¹H NMR. In isolation of the product, the reaction solutionwas condensed, and the condensed residue was dissolved in water, and theresulting water was made to pass through a cation exchange resin (DOWEX50W-X2). After flowing 50 mL of water, 200 mL of 0.1M aqueous ammoniawas flown, and the solution was condensed to give glutamic acid.

Referential Example 4

3.2 mmol of formate acid ammonium was poured into 3 mL of water so as tohave the pH 4.5. 0.2 mmol of (η⁵-tetramethylcyclopentadienyl) rhodium(III) (2,2′-bipyridyl) aqua complex and 0.2 μmol of ethyl acetoacetatewhose R¹ is CH₃ and R² is C₂H₅ in FIG. 2( b) were poured into theprepared formate ammonium aqueous solution, and the resulting mixturewas reacted at 80° C. under argon atmosphere for an hour. Aftercompletion of the reaction, the pH of the reaction solution was adjustedto 9.0. Thereafter, extraction and condensation were performed withdichloromethane or diethyl ether to give a product. The resultingproduct was analyzed by ¹H NMR. In isolation of the product, thereaction solution was condensed, and the condensed residue was dissolvedin water, and the resulting water was made to pass through a cationexchange resin (DOWEX 50W-X2). After flowing 50 mL of water, 200 mL of0.1M aqueous ammonia was flown, and the solution was condensed to give3-aminobutanate ethyl.

[Results of Referential Examples 1 to 4]

TABLE 4 Yield R¹ R² Cat Path TON mol % (%) Referential CH₃ Hwater-soluble Cp*Rh^(III)(bpy)(OH₂) B 750 0.13 94 Example 1 ReferentialC₆H₄(OH) H water-soluble Cp*Rh^(III)(bpy)(OH₂) B 350 0.13 44 Example 2Referential (CH₂)₂COOH H water-soluble Cp*Rh^(III)(bpy)(OH₂) B 300 0.1338 Example 3 Referential CH₃ C₂H₅ water-insoluble Cp*Rh^(III)(bpy)(OH₂)D 70 1 70 Example 4

In Table 4, “mol %” represents mol % of each catalyst with respect tothe keto acids, and “Yield (%)” represents an yield of amino acidsproduced from the keto acids. Other items are the same as in Table 1.

Table 4 shows that amino acids can be efficiently synthesized byreductive amination of keto acids in the presence of a transition metalcomplex ((η⁵-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl)aqua complex). Also, Table 4 shows that amino acids can be synthesizedregardless of whether the keto acids are water-soluble keto acids(Referential Examples 1 to 3) or water-insoluble keto-acid ester(Referential Example 4).

Further, the turnover number of the catalyst was high, which shows thatthe method in Referential Examples is extremely excellent. Particularlyin case of Referential Example 1, the resulting amino acids were formedat such an extremely high yield as 94%. In this way, the method isexcellent in selectivity with respect to synthesis of amino acids.

<3. Method for One-Pot Synthesis of Amino Acids FromAcetylene-Carboxylic Acids>

Synthesis of keto acids by the hydration and synthesis of amino acids byreductive amination of the keto acids were sequentially performed tocarry out one-pot synthesis of amino acids from acetylene-carboxylicacids. Each of FIG. 3( a) and FIG. 3( b) shows a reaction formula of thereaction. Note that, when water-soluble acetylene-carboxylic acids wereused as starting material, α-keto acids were synthesized to finally giveα-amino acids (FIG. 3( a)), and when water-insolubleacetylene-carboxylic acids were used as starting material, β-keto acidswere synthesized to finally give β-amino acids (FIG. 3( b)).

Example 16

5 mmol of water-soluble acetylene-carboxylic acids whose R¹ and R² are Hin FIG. 3 was poured into 10 mL of water so as to have the pH 2.0. 5.0μmol of rhodium chloride was added to the solution, and the resultingmixture was reacted at 80° C. under argon atmosphere. After 36 hours, 10mmol of formate ammonium and 5.0 μmol ofaqua(η⁵-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl)sulphate were added, and the resulting mixture was further reacted fortwo hours. After completion of the reaction, the resulting product wasanalyzed by ¹H NMR.

Example 17

5 mmol of water-soluble acetylene-carboxylic acids whose R¹ and R² are Hin FIG. 3 was poured into 10 mL of water so as to have the pH 2.0. 5.0μmol of ruthenium chloride was added to the solution, and the resultingmixture was reacted at 80° C. under argon atmosphere. After 36 hours, 10mmol of formate ammonium and 5.0 μmol ofaqua(η⁵-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl)sulphate were added, and the resulting mixture was further reacted fortwo hours. After completion of the reaction, the resulting product wasanalyzed by ¹H NMR.

Example 18

5 mmol of water-soluble acetylene-carboxylic acids whose R¹ is CH₃ andR² is H in FIG. 3 was poured into 10 mL of water so as to have the pH2.0. 5.0 μmol of ruthenium chloride was added to the solution, and theresulting mixture was reacted at 80° C. under argon atmosphere. After 36hours, 10 mmol of formate ammonium and 5.0 μmol ofaqua(η⁵-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl)sulphate were added, and the resulting mixture was further reacted fortwo hours. After completion of the reaction, the resulting product wasanalyzed by ¹H NMR.

Example 19

5 mmol of water-soluble acetylene-carboxylic acids whose R¹ is CH₃ andR² is H in FIG. 3 was poured into 10 mL of water so as to have the pH2.0. 5.0 μmol of ruthenium chloride was added to the solution, and theresulting mixture was reacted at 80° C. under argon atmosphere. After 36hours, 10 mmol of formate ammonium and 5.0 μmol of(η⁵-tetramethylcyclopentadienyl) rhodium (III) (2,2′-bipyridyl) aquacomplex were added, and the resulting mixture was further reacted fortwo hours. After completion of the reaction, the resulting product wasanalyzed by ¹H NMR.

Example 20

0.1 mmol of water-insoluble acetylene-dicarboxylic acids whose R¹ is CH₃and R² is C₂H₅ in FIG. 3 was poured into 10 mL of water so as to havethe pH 2.0. 5.0 μmol of rhodium chloride was added to the solution, andthe resulting mixture was reacted at 80° C. under argon atmosphere.After 12 hours, 10 mmol of formate ammonium and 1.0 μmol of(η⁵-tetramethylcyclopentadienyl) rhodium (III) (2,2′-bipyridyl) aquacomplex were added, and the resulting mixture was further reacted fortwo hours. After completion of the reaction, the resulting product wasanalyzed by ¹H NMR.

[Results of Examples 16 to 20]

Table 5 shows the results.

TABLE 5 Cat(mol %) reductive Yield R¹ R² hydration amination Path TON(%) Example H H water-soluble RhCl₃ Cp*Rh^(III)(bpy)(OH₂) A + B 130 1316 0.1 0.1 Example H H water-soluble RuCl₃ Cp*Rh^(III)(bpy)(OH₂) A + B280 28 17 0.1 0.1 Example CH₃ H water-soluble RuCl₃Cp*Rh^(III)(bpy)(OH₂) A + B 110 11 18 0.1 0.1 Example CH₃ Hwater-soluble RuCl₃ Cp*Rh^(III)(bpy)(OH₂) A + B 10 1 19 0.1 0.1 ExampleCH₃ C₂H₅ water-insoluble RhCl₃ 5 Cp*Rh^(III)(bpy)(OH₂) 1 C + D 7 35 20

In Table 5, a numerical value indicated below each catalyst in “Cat (mol%) represents mol % of the catalyst with respect to acetylene-carboxylicacids, and “Yield (%)” represents an yield of amino acids synthesizedfrom acetylene-carboxylic acids. Other items are the same as in Table 1.

Table 5 shows that one-pot synthesis of amino acids can be performed byusing any one of the water-soluble substances (Examples 16 to 19) andthe water-insoluble substance (Example 20).

Example 37

0.1 mmol of water-soluble acetylene-carboxylic acids whose R¹ and R² areH in FIG. 3 was poured into 2 mL of water so as to have the pH 1.3. 1.0μmol of ruthenium chloride was added to the solution, and the resultingmixture was reacted at 100° C. under argon atmosphere. After 12 hours, 4mmol of formate ammonium and 1.0 μmol ofaqua(η⁵-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl)sulphate were added, and the resulting mixture was further reacted at80° C. for an hour. After completion of the reaction, the resultingproduct was analyzed by ¹H NMR.

Example 38

0.1 mmol of water-soluble acetylene-carboxylic acids whose R¹ and R² areH in FIG. 3 was poured into 2 mL of water so as to have the pH 1.3. 1.0μmol of ruthenium chloride was added to the solution, and the resultingmixture was reacted at 100° C. under argon atmosphere. After 12 hours, 4mmol of formate ammonium and 0.1 μmol ofaqua(η⁵-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl)sulphate were added, and the resulting mixture was further reacted at80° C. for an hour. After completion of the reaction, the resultingproduct was analyzed by ¹H NMR.

Example 39

0.1 mmol of water-soluble acetylene-carboxylic acids whose R¹ and R² areH in FIG. 3 was poured into 2 mL of water so as to have the pH 1.3. 1.0μmol of ruthenium chloride was added to the solution, and the resultingmixture was reacted at 100° C. under argon atmosphere. After 12 hours, 4mmol of formate ammonium and 1.0 μmol ofaqua(η⁵-tetramethylcyclopentadienyl) iridium (III)(2,2′-bipyridyl)sulfate were added, and the resulting mixture was further reacted at 80°C. for one hour. After completion of the reaction, the resulting productwas analyzed by ¹H NMR.

Example 40

0.1 mmol of water-soluble acetylene-carboxylic acids whose R¹ is CH₃ andR² is H in FIG. 3 was poured into 2 mL of water so as to have the pH1.3. 1.0 μmol of ruthenium chloride was added to the solution, and theresulting mixture was reacted at 100° C. under argon atmosphere. After12 hours, 4 mmol of formate ammonium and 1.0 μmol ofaqua(η⁵-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl)sulphate were added, and the resulting mixture was further reacted at80° C. for an hour. After completion of the reaction, the resultingproduct was analyzed by ¹H NMR.

Example 41

0.1 mmol of water-soluble acetylene-carboxylic acids whose R¹ is CH₃ andR2 is H in FIG. 3 was poured into 2 mL of water so as to have the pH1.3. 1.0 μmol of ruthenium chloride was added to the solution, and theresulting mixture was reacted at 100° C. under argon atmosphere. After12 hours, 4 mmol of formate ammonium and 1.0 μmol ofaqua(η⁵-tetramethylcyclopentadienyl) iridium (III)(2,2′-bipyridyl)sulphate were added, and the resulting mixture was further reacted at80° C. for an hour. After completion of the reaction, the resultingproduct was analyzed by ¹H NMR.

Example 42

0.1 mmol of water-insoluble acetylene-carboxylic acids whose R¹ is CH₃and R² is C₂H₅ in FIG. 3 was poured into 2 mL of water so as to have thepH 4.0. 1.0 μmol of iridium chloride was added to the solution, and theresulting mixture was reacted at 80° C. under argon atmosphere. After 24hours, 4 mmol of formate ammonium and 1.0 μmol ofaqua(η⁵-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl)sulphate were added, and the resulting mixture was further reacted at80° C. for an hour. After completion of the reaction, the resultingproduct was analyzed by ¹H NMR.

Example 43

0.1 mmol of water-insoluble acetylene-carboxylic acids whose R¹ is CH₃and R² is C₂H₅ in FIG. 3 was poured into 2 mL of water so as to have thepH 4.0. 1.0 μmol of iridium chloride was added to the solution, and theresulting mixture was reacted at 80° C. under argon atmosphere. After 24hours, 4 mmol of formate ammonium and 1.0 μmol ofaqua(η⁵-tetramethylcyclopentadienyl) iridium (III) (2,2′-bipyridyl)sulphate were added, and the resulting mixture was further reacted at80° C. for an hour. After completion of the reaction, the resultingproduct was analyzed by ¹H NMR.

[Results of Examples 37 to 43]

Table 6 shows the results. See Table 6 in the same manner as in Table 5.

TABLE 6 Cat (mol %) reductive Yield R¹ R² hydration amination Path TON(%) Example H H water-soluble RuCl₃ 1 Cp*Rh^(III)(bpy)(OH₂) 1 A + B 7777 37 Example H H water-soluble RuCl₃ 1 Cp*Rh^(III)(bpy)(OH₂) 1 A + B 6060 38 Example H H water-soluble RuCl₃ 1 Cp*Ir^(III)(bpy)(OH₂) 1 A + B 8080 39 Example CH₃ H water-soluble RuCl₃ 1 Cp*Rh^(III)(bpy)(OH₂) 1 A + B40 40 40 Example CH₃ H water-soluble RuCl₃ 1 Cp*Ir^(III)(bpy)(OH₂) 1 A +B 36 36 41 Example CH₃ C₂H₅ water-insoluble IrCl₃ 1Cp*Rh^(III)(bpy)(OH₂) 1 C + D 12 12 42 Example CH₃ C₂H₅ water-insolubleIrCl₃ 1 Cp*Ir^(III)(bpy)(OH₂) 1 C + D 4.3 4.3 43

Table 6 shows that one-pot synthesis of amino acids can be performed byusing any one of the water-soluble substances (Examples 37 to 41) andthe water-insoluble substances (Examples 42 to 43). Particularly in caseof Examples 37, 38, and 39, the amino-acid yields (%) and turnovernumbers are respectively 77, 60, and 80. These are extremely favorableresults.

INDUSTRIAL APPLICABILITY

According to the present invention, keto acids can be easily synthesizedfrom acethyl-carboxylic acids. Further, amino acids can be easilysynthesized from the keto acids. Moreover, amino acids can besequentially synthesized from acethyl-carboxylic acids in a singlecontainer. The amino acids are extremely significant in living organismssuch as a human.

Therefore, the present invention is applicable to an industry producingamino acids, e.g., a pharmaceutical industry, a research reagentindustry, and a food industry, in particular.

1. A method for synthesis of keto acids, comprising the step ofhydrating acetylene-carboxylic acids in the presence of at least oneselected from a group consisting of a metal salt represented by GeneralFormula (1), a transition metal complex represented by General Formula(2), a transition metal complex represented by General Formula (3), anda transition metal complex represented by General Formula (8), a centralmetal element of said at least one being Ru,

where M¹ represents Ru, and X¹, X², or X³ ligand represents halogen,H₂O, or a solvent molecule, and k represents a valence of a cationspecies, and Y represents an anion species, and L represents a valenceof the anion species, and each of K and L independently represents 1 or2, and k×m=L×n,

where each of R¹ and R² independently represents a hydrogen atom or alower alkyl group, and M² represents Ru, and X¹ or X² ligand representsH₂O, halogen, a solvent molecule, or nitrous ligand, and X³ ligandrepresents halogen, H₂O, or a solvent molecule, and k represents avalence of a cation species, and Y represents an anion species, and Lrepresents a valence of the anion species, and each of K and Lindependently represents 1 or 2, and k×m=L×n,

where each of R¹, R², R³, R⁴, and R⁵ independently represents a hydrogenatom or a lower alkyl group, and M³ represents Ru, and each of X¹ and X²represents nitrous ligand, and X³ represents a hydrogen atom, acarboxylic acid residue, or H₂O, and X¹ and X² may be bonded to eachother, and k represents a valence of a cation species, and Y representsan anion species, and L represents a valence of the anion species, andeach of K and L independently represents 1 or 2, and k×m=L×n,

were each of R¹, R², R³, R⁴, R⁵ and R₆ independently represents ahydrogen atom or a lower alkyl group, and M represents Ru, and each ofX¹, X² and X³ represents halogen, H₂O, or a solvent molecule, and krepresents a valence of a cation species, and Y represents an anionspecies, and L represents a valence of the anion species, and each of Kand L independently represents 1 or 2, and k×m=L×n. 2.-3. (canceled) 4.The method as set forth in claim 1, wherein the hydration is performedin the presence of an organic solvent which is inert in reaction.
 5. Amethod for synthesis of amino acids, comprising the steps of: hydratingacetylene-carboxylic acids in the presence of a metal salt whose centralmetal element is Ru and which is represented by General Formula (1); andadding a transition metal complex whose central metal element is Ru andwhich is represented by General Formula (3) and a hydrogen and nitrogenatom donor to a reaction system of the hydrated acetylene-carboxylicacids so as to cause a reaction thereof,

where M¹ represents Ru, and X¹ or X² ligand represents halogen, H₂O, ora solvent molecule, and k represents a valence of a cation species, andY represents an anion species, and L represents a valence of the anionspecies, and each of K and L independently represents 1 or 2, andk×m=L×n,

where each of R¹, R², R³, R⁴, and R⁵ independently represents a hydrogenatom or a lower alkyl group, and M³ represents Ru, and each of X¹ and X²represents nitrous ligand, and X³ represents a hydrogen atom, acarboxylic acid residue, or H₂O, and X¹ and X² may be bonded to eachother, and k represents a valence of a cation species, and Y representsan anion species, and L represents a valence of the anion species, andeach of K and L independently represents 1 or 2, and k×m=L×n.
 6. Amethod for synthesis of amino acids, comprising the steps of: hydratingacetylene-carboxylic acids in the presence of a transition metal complexwhose central metal element is Ru and which is represented by GeneralFormula (2); and adding a transition metal complex whose central metalelement is Ru and which is represented by General Formula (3) and anitrogen atom donor to a reaction system of the hydratedacetylene-carboxylic acids so as to cause a reaction thereof,

where each of R¹ and R² independently represents a hydrogen atom or alower alkyl group, and M² represents Ru, and X¹ or X² ligand representsH₂O, halogen, a solvent molecule, or nitrous ligand, and X³ ligandrepresents halogen, H₂O, or a solvent molecule, and k represents avalence of a cation species, and Y represents an anion species, and Lrepresents a valence of the anion species, and each of K and Lindependently represents 1 or 2, and k×m=L×n,

where each of R¹, R², R³, R⁴, and R⁵ independently represents a hydrogenatom or a lower alkyl group, and M³ represents Ru, and each of X¹ and X²represents nitrous ligand, and X³ represents a hydrogen atom, acarboxylic acid residue, or H₂O, and X¹ and X² may be bonded to eachother, and k represents a valence of a cation species, and Y representsan anion species, and L represents a valence of the anion species, andeach of K and L independently represents 1 or 2, and k×m=L×n.
 7. Amethod for synthesis of amino acids, comprising the steps of: hydratingacetylene-carboxylic acids in the presence of at least one selected froma group consisting of a transition metal complex represented by GeneralFormula (2), a transition metal complex represented by General Formula(3), and a transition metal complex represented by General Formula (8),a central metal element of said at least one being Ru; and adding ahydrogen and nitrogen atom donor to a reaction system of the hydratedacetylene-carboxylic acids so as to cause a reaction thereof,

where each of R¹ and R² independently represents a hydrogen atom or alower alkyl group, and M² represents Ru, and X¹ or X² ligand representsH₂O, halogen, a solvent molecule, or nitrous ligand, and X³ ligandrepresents halogen, H₂O, or a solvent molecule, and k represents avalence of a cation species, and Y represents an anion species, and Lrepresents a valence of the anion species, and each of K and Lindependently represents 1 or 2, and k×m=L×n,

where each of R¹, R², R³, R⁴, and R⁵ independently represents a hydrogenatom or a lower alkyl group, and M³ represents Ru, and each of X¹ and X²represents nitrous ligand, and X³ represents a hydrogen atom, acarboxylic acid residue, and X¹ and X² may be bonded to each other, andk represents a valence of a cation species, and Y represents an anionspecies, and L represents a valence of the anion species, and each of Kand L independently represents 1 or 2, and k×m=L×n,

where each of R¹, R^(2,) R³, R⁴, R⁵ and R⁶ independently represents ahydrogen atom or a lower alkyl group, and M represents Ru, and each ofX¹, X² and X³ represents halogen, H₂O, or a solvent molecule, and krepresents a valence of a cation species, and Y represents an anionspecies, and L represents a valence of the anion species, and each of Kand L independently represents 1 or 2, and k×m=L×n.
 8. A method forsynthesis of amino acids, comprising the steps of: hydratingacetylene-carboxylic acids in the presence of a metal salt whose centralmetal element is Ru and which is represented by General Formula (1); andadding organic ligand respectively represented by General Formula (4)and General Formula (5) and a hydrogen and nitrogen atom donor to areaction system of the hydrated acetylene-carboxylic acids so as tocause a reaction thereof,

where M¹ Ru, and X¹, X², or X³ ligand represents halogen, H₂O, or asolvent molecule, and k represents a valence of a cation species, and Yrepresents an anion species, and L represents a valence of the anionspecies, and each of K and L independently represents 1 or 2, andk×m=L×n,

where each of R¹, R², R³, R⁴, and R⁵ independently represents a hydrogenatom or a lower alkyl group,

where each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ independentlyrepresents a hydrogen atom or a lower alkyl group.